Pyrimidinones as pi3k inhibitors

ABSTRACT

The present invention provides pyrimidinones that modulate the activity of phosphoinositide 3-kinases (PI3Ks) and are useful in the treatment of diseases related to the activity of PI3Ks including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.

This application is a continuation of U.S. Ser. No. 12/824,924, filedJun. 28, 2010, which claims the benefit of priority of U.S. Prov. Appl.No. 61/221,160, filed on Jun. 29, 2009, and U.S. Prov. Appl. No.61/259,765, filed on Nov. 10, 2009, each of which is incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The present invention provides pyrimidinones that modulate the activityof phosphoinositide 3-kinases (PI3Ks) and are useful in the treatment ofdiseases related to the activity of PI3Ks including, for example,inflammatory disorders, immune-based disorders, cancer, and otherdiseases.

BACKGROUND OF THE INVENTION

The phosphoinositide 3-kinases (PI3Ks) belong to a large family of lipidsignaling kinases that phosphorylate phosphoinositides at the D3position of the inositol ring (Cantley, Science, 2002,296(5573):1655-7). PI3Ks are divided into three classes (class I, II,and III) according to their structure, regulation and substratespecificity. Class I PI3Ks, which include PI3Kα, PI3Kβ, PI3Kγ, andPI3Kδ, are a family of dual specificity lipid and protein kinases thatcatalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate(PIP₂) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP₃).PIP₃ functions as a second messenger that controls a number of cellularprocesses, including growth, survival, adhesion and migration. All fourclass I PI3K isoforms exist as heterodimers composed of a catalyticsubunit (p110) and a tightly associated regulatory subunit that controlstheir expression, activation, and subcellular localization. PI3Kα,PI3Kβ, and PI3Kδ associate with a regulatory subunit known as p85 andare activated by growth factors and cytokines through a tyrosinekinase-dependent mechanism (Jimenez, et al., J Biol Chem., 2002,277(44):41556-62) whereas PI3Kγ associates with two regulatory subunits(p101 and p84) and its activation is driven by the activation ofG-protein-coupled receptors (Brock, et al., J Cell Biol., 2003,160(1):89-99). PI3Kα and PI3Kβ are ubiquitously expressed. In contrast,PI3Kγ and PI3Kδ are predominantly expressed in leukocytes(Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204).

The differential tissue distribution of the PI3K isoforms factors intheir distinct biological functions. Genetic ablation of either PI3Kα orPI3Kβ results in embryonic lethality, indicating that PI3Kα and PI3Kβhave essential and non-redundant functions, at least during development(Vanhaesebroeck, et al., 2005). In contrast, mice which lack PI3Kγ andPI3Kδ are viable, fertile and have a normal life span although they showan altered immune system. PI3Kγ deficiency leads to impaired recruitmentof macrophages and neutrophils to sites of inflammation as well asimpaired T cell activation (Sasaki, et al., Science, 2000,287(5455):1040-6). PI3Kδ-mutant mice have specific defects in B cellsignaling that lead to impaired B cell development and reduced antibodyresponses after antigen stimulation (Clayton, et al., J. Exp. Med. 2002,196(6):753-63; Jou, et al., Mol. Cell Biol. 2002, 22(24):8580-91;Okkenhaug, et al., Science, 2002, 297(5583):1031-4).

The phenotypes of the PI3Kγ and PI3Kδ-mutant mice suggest that theseenzymes may play a role in inflammation and other immune-based diseasesand this is borne out in preclinical models. PI3Kγ-mutant mice arelargely protected from disease in mouse models of rheumatoid arthritis(RA) and asthma (Camps, et al., Nat Med. 2005, 11(9):936-43; Thomas, etal., Eur. J. Immunol., 2005, 35(4):1283-91). In addition, treatment ofwild-type mice with a selective inhibitor of PI3Kγ was shown to reduceglomerulonephritis and prolong survival in the MRL-lpr model of systemiclupus nephritis (SLE) and to suppress joint inflammation and damage inmodels of RA (Barber, et al., Nat Med. 2005, 11(9):933-5; Camps, et al.,2005). Similarly, both PI3Kδ-mutant mice and wild-type mice treated witha selective inhibitor of PI3Kδ have been shown to have attenuatedallergic airway inflammation and hyper-responsiveness in a mouse modelof asthma (Ali, et al., Nature. 2004, 431(7011):1007-11; Lee, et al.,FASEB J. 2006, 20(3):455-65) and to have attenuated disease in a modelof RA (Randis, et al., Eur. J. Immunol., 2008, 38(5):1215-24).

In addition to their potential role in inflammatory diseases, all fourclass I PI3K isoforms may play a role in cancer. The gene encoding p110αis mutated frequently in common cancers, including breast, prostate,colon and endometrial (Samuels, et al., Science, 2004, 304(5670):554;Samuels, et al., Curr. Opin. Oncol. 2006, 18(1):77-82). Eighty percentof these mutations are represented by one of three amino acidsubstitutions in the helical or kinase domains of the enzyme and lead toa significant upregulation of kinase activity resulting in oncogenictransformation in cell culture and in animal models (Kang, et al., Proc.Natl. Acad. Sci. U.S.A. 2005, 102(3):802-7; Bader, et al., Proc. Natl.Acad. Sci. U.S.A. 2006, 103(5):1475-9). No such mutations have beenidentified in the other PI3K isoforms although there is evidence thatthey can contribute to the development and progression of malignancies.Consistent overexpression of PI3Kδ is observed in acute myeloblasticleukemia (Sujobert, et al., Blood, 2005, 106(3):1063-6) and inhibitorsof PI3Kδ can prevent the growth of leukemic cells (Billottet, et al.,Oncogene. 2006, 25(50):6648-59). Elevated expression of PI3Kγ is seen inchronic myeloid leukemia (Hickey, et al., J. Biol. Chem. 2006,281(5):2441-50). Alterations in expression of PI3Kβ, PI3Kγ and PI3Kδhave also been observed in cancers of the brain, colon and bladder(Benistant, et al., Oncogene, 2000, 19(44):5083-90; Mizoguchi, et al.,Brain Pathol. 2004, 14(4):372-7; Knobbe, et al., Neuropathol. Appl.Neurobiol. 2005, 31(5):486-90). Further, these isoforms have all beenshown to be oncogenic in cell culture (Kang, et al., 2006).

Thus, new or improved agents which inhibit kinases such as PI3K arecontinually needed for developing new and more effective pharmaceuticalsthat are aimed at augmentation or suppression of the immune andinflammatory pathways (such as immunosuppressive agents for organtransplants), as well as agents for the prevention and treatment ofautoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis,asthma, type I diabetes, inflammatory bowel disease, Crohn's disease,autoimmune thyroid disorders, Alzheimer's disease, nephritis), diseasesinvolving a hyperactive inflammatory response (e.g., eczema), allergies,lung diseases, cancer (e.g., prostate, breast, leukemia, multiplemyeloma), and some immune reactions (e.g., skin rash or contactdermatitis or diarrhea) caused by other therapeutics. The compounds,compositions, and methods described herein are directed toward theseneeds and other ends.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, compounds of Formula I orII:

or pharmaceutically acceptable salts thereof, wherein constituentmembers are defined herein.

The present invention further provides pharmaceutical compositionscomprising a compound of Formula I or II, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present invention further provides methods of modulating an activityof one or more kinases (such as a PI3K) comprising contacting the kinasewith a compound of Formula I or II, or a pharmaceutically acceptablesalt thereof.

The present invention further provides methods of treating a disease ora disorder associated with abnormal kinase expression or activity in apatient by administering to a patient a therapeutically effective amountof a compound of Formula I or II, or a pharmaceutically acceptable saltof the same.

The present invention further provides methods of treating diseases suchas immune-based diseases, cancer, and lung diseases in a patient byadministering to the patient a therapeutically effective amount of acompound of Formula I or II, or a pharmaceutically acceptable saltthereof.

The present invention further provides a compound of Formula I or II, ora pharmaceutically acceptable salt thereof, for use in therapy.

The present invention further provides use of a compound of Formula I orII, or a pharmaceutically acceptable salt thereof, for the production ofa medicament for use in therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. X-ray crystal structure of Example 15, step 5.

FIG. 2. X-ray crystal structure lattice of Example 15, step 5.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds that modulate theactivity of one or more PI3Ks and are useful, for example, in thetreatment of various diseases such as those associated with expressionor activity of one or more PI3Ks. The compounds of the invention includethose of Formula I or II:

or pharmaceutically acceptable salts thereof, wherein:

A is C₁₋₁₀ alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl,each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

L is absent, (CR^(7a)R^(7b))_(m),(CR^(7a)R^(7b))_(p)O(CR^(7a)R^(7b))_(q),(CR^(7a)R^(7b))_(p)S(CR^(7a)R^(7b))_(q), (CR^(7a)R^(7b))_(p)S(O)(CR^(7a)R^(7b))_(q), (CR^(7a)R^(7b))_(p)S(O)₂(CR^(7a)R^(7b))_(q),(CR^(7a)R^(7b))_(p)NR^(7c)(CR^(7a)R^(7b))_(q),(CR^(7a)R^(7b))_(p)NR^(7c)C(O)NR^(7c)(CR^(7a)R^(7b))_(q),(CR^(7a)R^(7b))_(p)NR^(7c)C(O)O(CR^(7a)R^(7b))_(q),(CR^(7a)R^(7b))_(p)NR^(7c)C(═NR^(7d))NR^(7c)(CR^(7a)R^(7b))_(q), or(CR^(7a)R^(7b))_(p)NR^(7c)S(O)₂(CR^(7a)R^(7b))_(q);

W is N or CR³;

X is N or CR⁴;

Y is N or CR⁵;

Z is N or CR⁶;

G is O, S, or NR^(N);

R¹ is OR^(A), SR^(A), S(O)R^(A), S(O)₂R^(A), NR^(A)R^(B),NR^(C)C(O)NR^(A)R^(B), NR^(C)C(O)OR^(A), NR^(C)C(═NR^(E))NR^(A)R^(B),NR^(C)S(O)₂R^(A), NR^(C)S(O)₂NR^(C)R^(A), heterocycloalkyl, orheteroaryl, wherein the heterocycloalkyl or heteroaryl is optionallysubstituted with 1, 2, or 3 substituents independently selected from—(C₁₋₄ alkyl)_(r)-Cy¹, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), S(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1);

R^(2a) and R^(2b) are independently selected from H, halo, OH, CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

or R^(2a) and R^(2b) together with the carbon atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl ring or a 3-,4-, 5-, 6-, or 7-membered heterocycloalkyl ring, each optionallysubstituted by 1, 2, or 3 substituents independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl,CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R³, R⁴, R⁵, and R⁶ are independently selected from H, halo, CN, NO₂,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)₂NR^(c3)R^(d3), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e))NR^(c3)R^(d3),NR^(c3)C(═NR^(e))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3);

R^(7a) and R^(7b) are independently selected from H, halo, or C₁₋₄alkyl;

R^(7c) is H or C₁₋₄ alkyl;

R^(7d) is H, CN, NO₂, OR^(a5), SR^(b5), S(O)₂R^(b5), C(O)R^(b5),S(O)₂NR^(c5)R^(d5), or C(O)NR^(c5)R^(d5);

R^(A) is heteroaryl, heterocycloalkyl, heteroarylalkyl, orheterocycloalkylalkyl, each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from —(C₁₋₄ alkyl), —Cy¹, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R^(B) and R^(C) are independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, 3, 4, or 5 substituents independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

R^(E) is H, CN, NO₂, OR^(a5), SR^(b5), S(O)₂R^(b5), C(O)R^(b5),S(O)₂NR^(c5)R^(d5), or C(O)NR^(c5)R^(d5);

R^(N) is H or C₁₋₄ alkyl;

Cy¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R^(a), R^(b), R^(C), and R^(d) are independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or R^(c) and R^(d) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or aheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

R^(a1), R^(b1), R^(c1), and R^(d1) are independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or Rc¹ and R^(d1) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or aheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

R^(a2), R^(b2), R^(c2), and R^(d2) are independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

or RC² and R^(d2) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or aheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

R^(a3), R^(b3), R^(c3), and R^(d3) are independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5), NR⁵C(═NR^(f))NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

or R^(c3) and R^(d3) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or aheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, halo, C₁₋₆haloalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(f))NR^(c5)R^(d5), NR⁵C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

R^(e) and R^(f) are independently selected from H, CN, NO₂, OR^(a5),SR^(b5), S(O)₂R^(b5), C(O)R^(b5), S(O)₂NR^(c5)R^(d5), andC(O)NR^(c5)R^(d5);

R^(a5), R^(b5), R^(c5), and R^(d5) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

or R^(c5) and R^(d5) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group orheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

p is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4; and

r is 0 or 1.

In some embodiments, the compounds of the invention have Formula I.

In some embodiments, the compounds of the invention have Formula II.

In some embodiments, A is C₁₋₁₀ alkyl optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, A is aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, A is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), andS(O)₂NR^(c)R^(d); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halosulfanyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, L is absent.

In some embodiments, L is (CR^(7a)R^(7b))_(m),(CR^(7a)R^(7b))_(p)O(CR^(7a)R^(7b))_(q),(CR^(7a)R^(7b))_(p)S(CR^(7a)R^(7b))_(q), (CR^(7a)R^(7b))_(p)S(O)(CR^(7a)R^(7b))_(q), (CR^(7a)R^(7b))_(p)S(O)₂(CR^(7a)R^(7b))_(q),(CR^(7a)R^(7b))_(p)NR^(7c)(CR^(7a)R^(7b))_(q),(CR^(7a)R^(7b))_(p)NR^(7c)C(O)NR^(7c)(CR^(7a)R^(7b))_(q),(CR^(7a)R^(7b))_(p)NR^(7c)C(O)O(CR^(7a)R^(7b))_(q),(CR^(7a)R^(7b))_(p)NR⁷C(═NR^(7d))NR^(7c)(CR^(7a)R^(7b))_(q), or(CR^(7a)R^(7b))_(p)NR^(7c)S(O)₂(CR^(7a)R^(7b))_(q).

In some embodiments, L is (CR^(7a)R^(7b))_(m).

In some embodiments, W is N.

In some embodiments, W is CR³.

In some embodiments, X is N.

In some embodiments, X is CR⁴.

In some embodiments, Y is N.

In some embodiments, Y is CR⁵.

In some embodiments, Z is N.

In some embodiments, Z is CR⁶.

In some embodiments, not more than 2 of W, X, Y, or Z are N.

In some embodiments, not more than 3 of W, X, Y, or Z are N.

In some embodiments, one of W and X is N.

In some embodiments, G is O.

In some embodiments, G is S.

In some embodiments, G is NR^(N).

In some embodiments, R¹ is heteroaryl optionally substituted with 1, 2,or 3 substituents independently selected from —(C₁₋₄ alkyl)_(r)-Cy¹,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halosulfanyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments, R¹ is NR^(A)R^(B).

In some embodiments, R^(2a) and R^(2b) are independently selected from Hand C₁₋₆ alkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c1)S(O)₂R^(b2), NR^(c3)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, at least one of R^(2a) and R^(2b) is other than H.

In some embodiments, R³, R⁴, R⁵, and R⁶ are independently selected fromH or C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c5)C(O)OR^(a5), C(═NR^(e))NR^(c3)R^(d3),NR^(c3)C(═NR^(e))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3).

In some embodiments, R³ is C₁₋₆ alkyl optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3),C(═NR^(e))NR^(c3)R^(d3), NR^(c3)C(═NR^(e))NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c)R^(d3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, R⁴, R⁵, and R⁶ are each H.

In some embodiments, R^(7a), R^(7b), R^(7c), and R^(7d) are each H.

In some embodiments, R^(A) is heteroaryl optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(f))NR^(c5)R^(d5), NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5).

In some embodiments, R^(B) and R^(c) are independently selected from Hand C₁₋₆ alkyl.

In some embodiments, A is other than phenyl substituted at the4-position by halogen.

In some embodiments, r is 0.

In some embodiments, r is 1.

In some embodiments, the compounds of the invention have Formula Ia, Ib,Ic, Id, Ie, IIa, IIb, or IIc:

In some embodiments, the compounds of the invention have Formula If orIId:

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId:

A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), andS(O)₂NR^(c)R^(d); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halosulfanyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d), NR^(c)(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

R¹ is OR^(A), SR^(A), S(O)R^(A), S(O)₂R^(A), NR^(A)R^(B),NR^(C)C(O)NR^(A)R^(B), NR^(C)C(O)OR^(A), NR^(C)C(═NR^(E))NR^(A)R^(B),NR^(C)S(O)₂R^(A), NR^(C)S(O)₂NR^(C)R^(A), heterocycloalkyl, orheteroaryl, wherein the heterocycloalkyl or heteroaryl is optionallysubstituted with 1, 2, or 3 substituents independently selected from—(C₁₋₄ alkyl)_(r)-Cy¹, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R^(2a) is H, halo, OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein theC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NRe)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R³, R⁴, R⁵, and R⁶ are independently selected from H, halo, CN, NO₂,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)₂NR^(c3)R^(d3), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e))NR^(c3)R^(d3),NR^(c3)C(═NR^(e))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3);

R^(A) is heteroaryl, heterocycloalkyl, heteroarylalkyl, orheterocycloalkylalkyl, each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from —(C₁₋₄ alkyl)_(r)-Cy¹, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R^(B) and R^(C) are independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, 3, 4, or 5 substituents independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5), NR⁵C(═NR^(f))NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

R^(E) is H, CN, NO₂, OR^(a5), SR^(b5), S(O)₂R^(b5), C(O)R^(b5),S(O)₂NR^(c5)R^(d5), or C(O)NR^(c5)R^(d5);

Cy¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R^(a), R^(b), R^(c), and R^(d) are independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5), NR⁵C(═NR^(f))NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

or R^(c) and R^(d) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or aheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

R^(a1), R^(b1), R^(c1), and R^(d1) are independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),N^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5), NR⁵C(═NR^(f))NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or aheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

R^(a2), R^(b2), R^(c2), and R^(d2) are independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5), NR⁵C(═NR^(f))NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or aheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5);

R^(a3), R^(b3), R^(c3), and R^(d3) are independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5), NR⁵C(═NR^(f))NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

or R^(c3) and R^(d3) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or aheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, halo, C₁₋₆haloalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(f))NR^(c5)R^(d5), NR⁵C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);

R^(e) and R^(f) are independently selected from H, CN, NO₂, OR^(a5),SR^(b5), S(O)₂R^(b5), C(O)R^(b5), S(O)₂NR^(c5)R^(d5), andC(O)NR^(c5)R^(d5);

R^(a5), R^(b5), R^(c5), and R^(d5) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

or R^(c5) and R^(d5) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group orheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy; and

r is 0 or 1.

In some embodiments of compounds of Formulas I and Ia-If, when A is3-fluorophenyl; R^(2a) is H; R³ is methyl; and R⁴, R⁵, and R⁶ are H;then R¹ is other than 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl.

In some embodiments of compounds of Formulas I and Ia-If, when A is1,3-dioxolan-2-yl; R^(2a), R³, R⁴, and R⁶ are H; then R¹ is other than1-(tert-butoxycarbonyl)piperidin-4-yl.

In some embodiments of compounds of Formulas I and Ia-If, R¹ is otherthan a substituted or unsubstituted pyrazolo[3,4-d]pyrimidin-1-yl group.

In some embodiments of compounds of Formulas I and Ia-If, R¹ is otherthan a substituted or unsubstituted piperidinyl group.

In some embodiments, the compound has Formula Ia.

In some embodiments, the compound has Formula Ib.

In some embodiments, the compound has Formula Ic.

In some embodiments, the compound has Formula Id.

In some embodiments, the compound has Formula Ie.

In some embodiments, the compound has Formula If.

In some embodiments, the compound has Formula IIa.

In some embodiments, the compound has Formula IIb.

In some embodiments, the compound has Formula IIc.

In some embodiments, the compound has Formula IId.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is cycloalkyl or heterocycloalkyl, each optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, or5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is aryl optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NRCRd, NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is phenyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is heteroaryl optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is 6-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is pyridyl optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is 5-membered heteroaryl optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,A is pyrazolyl optionally substituted with 1 or 2 substituentsindependently selected from halo, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R¹ is heteroaryl optionally substituted with 1, 2, or 3 substituentsindependently selected from —(C₁₋₄ alkyl)_(r)-Cy¹, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R¹ is bicyclic heteroaryl optionally substituted with 1, 2, or 3substituents independently selected from —(C₁₋₄ alkyl)_(r)-Cy¹, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R¹ is purinyl optionally substituted with—(C₁₋₄ alkyl)_(r)-Cy¹, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R¹ is OR^(A), SR^(A), S(O)R^(A), S(O)₂R^(A), NR^(A)R^(B),NR^(C)C(O)NR^(A)R^(B), NR^(C)C(O)OR^(A), NR^(C)C(═NR^(E))NR^(A)R^(B),NR^(C)S(O)₂R^(A), or NR^(C)S(O)₂NR^(C)R^(A).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R¹ is NR^(A)R^(B).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(A) is heteroaryl optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from —(C₁₋₄ alkyl)_(r)-Cy¹, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR_(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(A) is bicyclic heteroaryl optionally substituted with 1, 2, 3, 4, or5 substituents independently selected from —(C₁₋₄ alkyl)_(r)-Cy¹, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)Rb¹,S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(A) is purinyl optionally substituted with 1 or 2 substituentsindependently selected from —(C₁₋₄ alkyl)_(r)-Cy¹, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(A) is purinyl optionally substituted with 1 or 2 substituentsindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(A) is:

In some embodiments, R^(A) is selected from:

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(A) is bicyclic heteroaryl optionally substituted with 1, 2, 3, 4, or5 substituents independently selected from (C₁₋₄ alkyl)_(r)-Cy¹, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(B) and R^(c) are independently selected from H and C₁₋₆ alkyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(B) and R^(c) are each H.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(2a) is H, halo, OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(2a) is halo, OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(2a) is H, halo, OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(2a) is C₁₋₆ alkyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R^(2a) is methyl or ethyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R³ is halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)₂NR^(c3)R^(d3), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e))NR^(c3)R^(d3),NR^(c3)C(═NR^(e))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R³ is H, halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3),S(O)₂NR^(c3)R^(d3), or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl, is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3),C(═NR^(e))NR^(c3)R^(d3), NR^(c3)C(═NR^(e))NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), andS(O)₂NR^(c3)R^(d3).

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R³ is H or C₁₋₆ alkyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R³ is C₁₋₆ alkyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R³ is methyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R⁴, R⁵, and R⁶ are independently selected from H, halo, C₁₋₆ alkyl, orC₁₋₆ haloalkyl.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R⁴, R⁵, and R⁶ are each H.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R⁴ is H.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R⁵ is H.

In some embodiments of compounds of Formulas I, Ia-If, II, and IIa-IId,R⁶ is H.

In some embodiments, the compounds of the invention have Formula Ig orIIe:

In some embodiments of compounds of Formulas Ig and He, R¹ is accordingto any of the previously recited embodiments for R¹.

In some embodiments, the compounds of the invention have Formula Ih orIIf:

In some embodiments, of compounds of Formulas Ih and IIf, R^(A) isaccording to any of the previously recited embodiments for R^(A).

In some embodiments, the compounds of the invention have Formula Ii orIIg:

wherein R⁸ and R⁹ are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(f))NR^(c5)R^(d5), NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5).

In some embodiments, R⁸ and R⁹ are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5), andNR^(c5)S(O)₂NR^(c5)R^(d5).

In some embodiments, R⁸ and R⁹ are independently selected from H andC₁₋₆ alkyl.

In some embodiments of compounds of Formulas Ig-Ii and IIe-IIg, A isaccording to any of the previously recited embodiments for A.

In some embodiments of compounds of Formulas Ig-Ii and IIe-IIg, R³ isaccording to any of the previously recited embodiments for R³.

In some embodiments of compounds of Formulas Ig-Ii and IIe-IIg, R^(2a)is according to any of the previously recited embodiments for R^(2a).

In some embodiments of compounds of Formulas Ig-Ii and IIe-IIg, R^(B) isaccording to any of the previously recited embodiments for R^(B).

In some embodiments of compounds of Formula If or IId:

A is aryl or heteroaryl, each optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, and OR^(a);

R¹ is NR^(A)R^(B) or heteroaryl; wherein the hetereoaryl is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, and OR^(a1);

R^(2a) is C₁₋₆ alkyl;

R³, R⁴, R⁵, and R⁶ are independently selected from H, halo, CN, NO₂,OR^(a3), and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo;

R^(A) is heteroaryl, which is optionally substituted with 1, 2, 3, 4, or5 substituents independently selected from halo, C₁₋₆ alkyl, CN,OR^(a1), and NR^(c1)R^(d1);

R^(B) is H;

each R^(a) is independently selected from H and C₁₋₆ alkyl;

each R^(a1), R^(c1), and R^(d1) is independently selected from H andC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from halo; and

each R^(a3) is independently selected from H and C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo.

In some embodiments of compounds of Formula If or IId:

A is phenyl, 5-membered heteroaryl or 6-membered heteroaryl, eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, and OR^(a);

R¹ is NR^(A)R^(B) or

R^(2a) is C₁₋₆ alkyl;

R³, R⁴, R⁵, and R⁶ are independently selected from H, halo, CN, NO₂,OR^(a3), and C₁₋₆ alkyl; wherein the C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo;

R^(A) is selected from:

R^(B) is H;

each R^(a) is independently selected from H and C₁₋₆ alkyl; and

each R^(a3) is independently selected from H and C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable sub combination.

At various places in the present specification, linking substituents aredescribed. It is specifically intended that each linking substituentinclude both the forward and backward forms of the linking substituent.For example, —NR(CR′R″)_(n)— includes both —NR(CR′R″)_(n)— and—(CR′R″)_(n)NR—. Where the structure clearly requires a linking group,the Markush variables listed for that group are understood to be linkinggroups. For example, if the structure requires a linking group and theMarkush group definition for that variable lists “alkyl” or “aryl” thenit is understood that the “alkyl” or “aryl” represents a linkingalkylene group or arylene group, respectively.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, t-butyl), pentyl(e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl), and the like. Analkyl group can contain from 1 to about 20, from 2 to about 20, from 1to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, orfrom 1 to about 3 carbon atoms.

As used herein, “alkenyl” refers to an alkyl group having one or morecarbon-carbon double bonds. Example alkenyl groups include ethenyl,propenyl, cyclohexenyl, and the like.

As used herein, “alkynyl” refers to an alkyl group having one or morecarbon-carbon triple bonds. Example alkynyl groups include ethynyl,propynyl, and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like.

As used herein, “halosulfanyl” refers to a sulfur group having one ormore halogen substituents. Example halosulfanyl groups includepentahalosulfanyl groups such as SF₅.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 20 carbonatoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings)groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl groupcan be optionally substituted by oxo or sulfido. Cycloalkyl groups alsoinclude cycloalkylidenes. Example cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl,norcarnyl, adamantyl, and the like. Also included in the definition ofcycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo or thienyl derivatives of cyclopentane, cyclopentene,cyclohexane, and the like. A cycloalkyl group containing a fusedaromatic ring can be attached through any ring-forming atom including aring-forming atom of the fused aromatic ring.

As used herein, “heteroaryl” refers to an aromatic heterocycle having atleast one heteroatom ring member such as sulfur, oxygen, or nitrogen.Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3or 4 fused rings) systems. Examples of heteroaryl groups include withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl,indolinyl, and the like. Examples of bicyclic heteroaryl groups includewithout limitation, purinyl, indolyl, and the like. In some embodiments,any ring-forming N in a heteroaryl moiety can be substituted by oxo. Insome embodiments, the heteroaryl group has from 1 to about 20 carbonatoms, and in further embodiments from about 3 to about 20 carbon atoms.In some embodiments, the heteroaryl group contains 3 to about 14, 4 toabout 14, 9 to about 10, or 5 to 6 ring-forming atoms. In someembodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to non-aromatic heterocycleshaving one or more ring-forming heteroatoms such as an O, N, or S atom.Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having2, 3 or 4 fused rings) systems as well as spirocycles. Example“heterocycloalkyl” groups include morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Ring-formingcarbon atoms and heteroatoms of a heterocycloalkyl group can beoptionally substituted by oxo or sulfido. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl,and benzo derivatives of heterocycles. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. The heterocycloalkyl group containing a fused aromatic ringcan be attached through any ring-forming atom including a ring-formingatom of the fused aromatic ring. In some embodiments, theheterocycloalkyl group has from 1 to about 20 carbon atoms, and infurther embodiments from about 3 to about 20 carbon atoms. In someembodiments, the heterocycloalkyl group contains 3 to about 14, 4 toabout 14, 3 to about 7, or 5 to 6 ring-forming atoms. In someembodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3,or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl groupcontains 0 to 3 double or triple bonds. In some embodiments, theheterocycloalkyl group contains 0 to 2 double or triple bonds.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “arylalkyl” refers to alkyl substituted by aryl and“cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. An examplearylalkyl group is benzyl.

As used herein, “heteroarylalkyl” refers to alkyl substituted byheteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted byheterocycloalkyl.

As used herein, “amino” refers to NH₂.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used herein, “haloalkoxy” refers to an —O-(haloalkyl) group.

As used herein, “alkylthio” refers to an —S-alkyl group. Examplealkylthio groups include meththio, ethylthio, propylthio (e.g.,n-propylthio and isopropylthio), and the like.

As used herein, “alkylamino” refers to an —NH-alkyl group. Examplealkylamino groups include methylamino, ethylamino, propylamino (e.g.,n-propylamino and isopropylamino), and the like.

As used herein, “di(alkyl)amino” refers to an —N(alkyl)₂ group. Exampledi(alkyl)amino groups include dimethylamino, diethylamino, dipropylamino(e.g., di(n-propyl)amino and di(isopropyl)amino), and the like.

It should be further appreciated that certain features of the invention,which are, for clarity, described in the context of separateembodiments, can also be provided in combination in a single embodiment.Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution. For example, purine includes the 9H and a 7H tautomericforms:

Compounds of the invention can include both the 9H and 7H tautomericforms.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g. a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (ACN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999), which is incorporated herein by referencein its entirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

Example synthetic methods for preparing compounds of the invention areprovided in the Schemes below. For instance, compounds of the inventioncan be prepared by the general synthetic procedure shown in Scheme 1.Heteroaryl compounds of formula 1 can react with4-halo-3-oxo-pentanoates 2 in the presence of polyphosphoric acid (PPA)to provide the compounds of formula 3 via a cyclocondensation reaction.These can be subjected to halogenation reaction under suitableconditions, to provide halogenated compounds 4. Compounds of formula 4can be transformed to the compounds of formula 5 through any variationof a sequence of steps. X¹ can be replaced with either an azide, anamine, or a heterocyclic group through an S_(N)2 displacement andeventually transformed to the R¹ group. X² can be converted to a desiredcyclic moiety (Cy) through any of the standard cross-coupling reactions,known to one skilled in the art, e.g., using boronic acid derivatives ofthe desired cyclic moiety.

As shown in Scheme 2, the pyrido[1,2-a]pyrimidin-4-ones of the inventioncan be prepared by cyclocondensation of aminopyrimidines 6 with a β-ketoester 2. Halogenation of the resultant pyridopyridinones 7 undersuitable conditions (such as NBS or bromine) provides compounds offormula 8. The latter can be transformed to the compounds of formula 9through an S_(N)2 subsitution of X¹ with a hetereocycle R¹ followed by acoupling reaction of X² with L-A moiety (such as a Negishi coupling oforganozinc reagent; a Suzuki or Stille coupling of an arylboronic acidor arylstanne, respectively). Alternatively, X¹ can be replaced witheither an amine or an azide which can be reduced to amine. The amine canthen be subjected to coupling reaction with a R¹ moiety to givecompounds of formula 9.

The thiazolo[3,2-a]pyrimidin-5-ones of the invention can be preparedaccording to Scheme 3. 2-Aminothiazole 10 condensed with a β-keto ester2 provides thiazolopyrimidinone 11. Compounds of formula 11 can beconverted to compounds of formula 13 through any variations of asequence of steps as described above.

Alternatively, compounds of the invention can be synthesized by reactingamino heterocycles 14 with an α-substituted β-keto ester 15 shown inScheme 4. The cyclocondensation derivatives 16 can then be subjected tohalogenation (such as NBS or bromine) or oxidation (such as SeO₂) toafford halogen compounds 17 (X¹=halogen), or alcohol compounds 17(X═OH), respectively. Compounds of formula 17 can then be transformed tocompounds of formula 18 through any variations of a sequence of steps.X¹ can be coupled directly with a heterocycles under any of the crosscoupling conditions know to one skilled in the art (such asBuchwald-Hartwig cross coupling conditions) or converted to a halogenthen the latter can be coupled with a heterocycles through S_(N)2substitutions.

Compounds of Formula II of the invention can be prepared according toScheme 5. Amino heterocycles 19 condensed with α-substituted β-ketoneester 15 affords compounds of formula 20. The latter can be transformedto compounds of Formula II through any variation of steps describedabove.

It should noted that in all of the Schemes described herein, if thereare functional groups present on a substituent group, furthermodification can be made if appropriate and desired. For example, a CNgroup can be hydrolyzed to afford an amide group; a carboxylic acid canbe converted to a ester, which in turn can be reduced to an alcohol,which in turn can be further modified. In another example, an OH groupcan be converted into a better leaving group such as mesylate, which inturn is suitable for nucleophilic substitution, such as by CN.Furthermore, an OH group can be subjected to Mitsunobu reactionconditions with phenol, or hetereoaryl alcohol, to afford aryl orheteroaryl ether compounds. One skilled in the art will recognizefurther modifications.

It should be further noted that the reaction sequences described abovecan be modified to suit different target molecules. For instance,Cy-boronic acid can be reacted with 4 to generate the Suzuki productfirst. The X¹ group of the Suzuki product can then be furtherfunctionalized with a nucleophilic reagent such as an azide or aheterocyclic amine.

Methods

The compounds of the invention can modulate activity of one or more ofvarious kinases including, for example, phosphoinositide 3-kinases(PI3Ks). The term “modulate” is meant to refer to an ability to increaseor decrease the activity of one or more members of the PI3K family.Accordingly, the compounds of the invention can be used in methods ofmodulating a PI3K by contacting the PI3K with any one or more of thecompounds or compositions described herein. In some embodiments,compounds of the present invention can act as inhibitors of one or morePI3Ks. In further embodiments, the compounds of the invention can beused to modulate activity of a PI3K in an individual in need ofmodulation of the receptor by administering a modulating amount of acompound of the invention, or a pharmaceutically acceptable saltthereof. In some embodiments, modulating is inhibiting.

Given that cancer cell growth and survival is impacted by multiplesignaling pathways, the present invention is useful for treating diseasestates characterized by drug resistant kinase mutants. In addition,different kinase inhibitors, exhibiting different preferences in thekinases which they modulate the activities of, may be used incombination. This approach could prove highly efficient in treatingdisease states by targeting multiple signaling pathways, reduce thelikelihood of drug-resistance arising in a cell, and reduce the toxicityof treatments for disease.

Kinases to which the present compounds bind and/or modulate (e g,inhibit) include any member of the PI3K family. In some embodiments, thePI3K is PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. In some embodiments, the PI3K isPI3Kγ or PI3Kδ. In some embodiments, the PI3K is PI3Kγ. In someembodiments, the PI3K is PI3Kδ. In some embodiments, the PI3K includes amutation. A mutation can be a replacement of one amino acid for another,or a deletion of one or more amino acids. In such embodiments, themutation can be present in the kinase domain of the PI3K.

In some embodiments, more than one compound of the invention is used toinhibit the activity of one kinase (e.g., PI3Kγ or PI3Kδ).

In some embodiments, more than one compound of the invention is used toinhibit more than one kinase, such as at least two kinases (e.g., PI3Kγor PI3Kδ.

In some embodiments, one or more of the compounds is used in combinationwith another kinase inhibitor to inhibit the activity of one kinase(e.g., PI3Kγ or PI3Kδ).

In some embodiments, one or more of the compounds is used in combinationwith another kinase inhibitor to inhibit the activities of more than onekinase (e.g., PI3Kγ or PI3Kδ), such as at least two kinases.

The compounds of the invention can be selective. By “selective” is meantthat the compound binds to or inhibits a kinase with greater affinity orpotency, respectively, compared to at least one other kinase. In someembodiments, the compounds of the invention are selective inhibitors ofPI3Kγ or PI3Kδ over PI3Kα and/or PI3Kβ. In some embodiments, thecompounds of the invention are selective inhibitors of PI3Kδ (e.g., overPI3Kα, PI3Kβ, and PI3Kγ). In some embodiments, the compounds of theinvention are selective inhibitors of PI3Kγ (e.g., over PI3Kα, PI3Kβ,and PI3Kδ). In some embodiments, selectivity can be at least about2-fold, 5-fold, 10-fold, at least about 20-fold, at least about 50-fold,at least about 100-fold, at least about 200-fold, at least about500-fold or at least about 1000-fold. Selectivity can be measured bymethods routine in the art. In some embodiments, selectivity can betested at the K_(m) ATP concentration of each enzyme. In someembodiments, the selectivity of compounds of the invention can bedetermined by cellular assays associated with particular PI3K kinaseactivity.

Another aspect of the present invention pertains to methods of treatinga kinase (such as PI3K)-associated disease or disorder in an individual(e.g., patient) by administering to the individual in need of suchtreatment a therapeutically effective amount or dose of one or morecompounds of the present invention or a pharmaceutical compositionthereof. A PI3K-associated disease can include any disease, disorder orcondition that is directly or indirectly linked to expression oractivity of the PI3K, including overexpression and/or abnormal activitylevels. In some embodiments, the disease can be linked to Akt (proteinkinase B), mammalian target of rapamycin (mTOR), orphosphoinositide-dependent kinase 1 (PDK1). In some embodiments, themTOR-related disease can be inflammation, atherosclerosis, psoriasis,restenosis, benign prostatic hypertrophy, bone disorders, pancreatitis,angiogenesis, diabetic retinopathy, arthritis, immunological disorders,kidney disease, or cancer. A PI3K-associated disease can also includeany disease, disorder or condition that can be prevented, ameliorated,or cured by modulating PI3K activity. In some embodiments, the diseaseis characterized by the abnormal activity of PI3K. In some embodiments,the disease is characterized by mutant PI3K. In such embodiments, themutation can be present in the kinase domain of the PI3K.

Examples of PI3K-associated diseases include immune-based diseasesinvolving the system including, for example, rheumatoid arthritis,allergy, asthma, glomerulonephritis, lupus, or inflammation related toany of the above.

Further examples of PI3K-associated diseases include cancers such asbreast, prostate, colon, endometrial, brain, bladder, skin, uterus,ovary, lung, pancreatic, renal, gastric, or hematological cancer.

In some embodiments, the hematological cancer is acute myeloblasticleukemia (AML) or chronic myeloid leukemia (CML), or B cell lymphoma.

Further examples of PI3K-associated diseases include lung diseases suchas acute lung injury (ALI) and adult respiratory distress syndrome(ARDS).

Further examples of PI3K-associated diseases include osteoarthritis,restenosis, atherosclerosis, bone disorders, arthritis, diabeticretinopathy, psoriasis, benign prostatic hypertrophy, inflammation,angiogenesis, pancreatitis, kidney disease, inflammatory bowel disease,myasthenia gravis, multiple sclerosis, or Sjoegren's syndrome, and thelike.

The present invention further provides a compound described herein, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound describedherein, or a pharmaceutically acceptable salt thereof, for theproduction of a medicament for use in any of the methods describedherein.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a PI3K with a compound of the invention includesthe administration of a compound of the present invention to anindividual or patient, such as a human, having a PI3K, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the PI3K.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) preventing the disease; for example, preventing a disease,condition or disorder in an individual who may be predisposed to thedisease, condition or disorder but does not yet experience or displaythe pathology or symptomatology of the disease; (2) inhibiting thedisease; for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology); and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

Combination Therapies

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, cKit, IGF-1R, RAF and FAK kinase inhibitors such as, forexample, those described in WO 2006/056399, or other agents such as,therapeutic antibodies can be used in combination with the compounds ofthe present invention for treatment of PI3K-associated diseases,disorders or conditions. The one or more additional pharmaceuticalagents can be administered to a patient simultaneously or sequentially.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present invention and are presented as a non limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa,Tarceva, antibodies to EGFR, Gleevec™, intron, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine,cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine,Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP,and MDL-101,731.

Example chemotherapeutics include proteosome inhibitors (e.g.,bortezomib), thalidomide, revlimid, and DNA-damaging agents such asmelphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include the compounds, and pharmaceuticallyacceptable salts thereof, of the genera and species disclosed in U.S.Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 03/037347, WO03/099771, and WO 04/046120.

Example suitable RAF inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO05/028444.

Example suitable FAK inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 04/080980, WO04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402.

In some embodiments, the compounds of the invention can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the invention can be used incombination with a chemotherapeutic in the treatment of cancer, such asmultiple myeloma, and may improve the treatment response as compared tothe response to the chemotherapeutic agent alone, without exacerbationof its toxic effects. Examples of additional pharmaceutical agents usedin the treatment of multiple myeloma, for example, can include, withoutlimitation, melphalan, melphalan plus prednisone [MP], doxorubicin,dexamethasone, and Velcade (bortezomib). Further additional agents usedin the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAKkinase inhibitors. Additive or synergistic effects are desirableoutcomes of combining a PI3K inhibitor of the present invention with anadditional agent. Furthermore, resistance of multiple myeloma cells toagents such as dexamethasone may be reversible upon treatment with thePI3K inhibitor of the present invention. The agents can be combined withthe present compound in a single or continuous dosage form, or theagents can be administered simultaneously or sequentially as separatedosage forms.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of theinvention where the dexamethasone is administered intermittently asopposed to continuously.

In some further embodiments, combinations of the compounds of theinvention with other therapeutic agents can be administered to a patientprior to, during, and/or after a bone marrow transplant or stem celltransplant.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.Coated condoms, gloves and the like may also be useful.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compounds or compositions of the inventioncontain from about 5 to about 50 mg of the active ingredient. One havingordinary skill in the art will appreciate that this embodies compoundsor compositions containing about 5 to about 10, about 10 to about 15,about 15 to about 20, about 20 to about 25, about 25 to about 30, about30 to about 35, about 35 to about 40, about 40 to about 45, or about 45to about 50 mg of the active ingredient.

In some embodiments, the compounds or compositions of the inventioncontain from about 50 to about 500 mg of the active ingredient. Onehaving ordinary skill in the art will appreciate that this embodiescompounds or compositions containing about 50 to about 100, about 100 toabout 150, about 150 to about 200, about 200 to about 250, about 250 toabout 300, about 350 to about 400, or about 450 to about 500 mg of theactive ingredient.

In some embodiments, the compounds or compositions of the inventioncontain from about 500 to about 1000 mg of the active ingredient. Onehaving ordinary skill in the art will appreciate that this embodiescompounds or compositions containing about 500 to about 550, about 550to about 600, about 600 to about 650, about 650 to about 700, about 700to about 750, about 750 to about 800, about 800 to about 850, about 850to about 900, about 900 to about 950, or about 950 to about 1000 mg ofthe active ingredient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as the judgment of the attending clinician depending upon factorssuch as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating PI3K in tissue samples,including human, and for identifying PI3K ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes PI3Kassays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I d ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro PI3K labeling and competition assays, compounds that incorporate³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be most useful. Forradio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Bror ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a PI3K by monitoring its concentrationvariation when contacting with the PI3K, through tracking of thelabeling. For example, a test compound (labeled) can be evaluated forits ability to reduce binding of another compound which is known to bindto a PI3K (i.e., standard compound). Accordingly, the ability of a testcompound to compete with the standard compound for binding to the PI3Kdirectly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of PI3K-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to be PI3Kinhibitors according to at least one assay described herein.

EXAMPLES

The example compounds below containing one or more chiral centers wereobtained in racemate form or as isomeric mixtures, unless otherwisespecified.

Example 12-[1-(6-amino-9H-purin-9-yl)ethyl]-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

Step 1. methyl 4-chloro-3-oxopentanoate

To a solution of 3-oxopentanoic acid, methyl ester (Aldrich, 26.0 mL,207.2 mmol) in methylene chloride (300 mL) was added in portions,N,N,N-trimethyl(phenyl) methanaminium dichloroiodanuide (75.71 g, 217.5mmol). The reaction mixture was stirred at room temperature (rt) for 2h, then washed with saturated sodium thiosulfate, brine, dried overmagnesium sulfate and concentrated. The crude product was used directlyin next step (23 g, 67.4%).

Step 2. 2-(1-chloroethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a manually stirred polyphosphoric acid (30 g, 200 mmol) in a 200 mLbeaker was added 6-methyl-2-pyridinamine (Aldrich, 4.7 g, 43 mmol),followed by methyl 4-chloro-3-oxopentanoate (8.584 g, 52.15 mmol). Themixture was heated with stirring at 110° C. for 5 h. After being cooled,the dark slurry was transferred on to 100 g of ice. The pH of themixture was adjusted to 6-7 with 10% sodium hydroxide. The mixture wasextracted with methylene chloride. The combined organic layers werewashed with water, brine, dried over magnesium sulfate and evaporated todryness. The residue was purified on silica gel, eluting with 0-10%methanol in methylene chloride, to yield the desired product (3.16 g,32.7%). LCMS calculated for C₁₁H₁₂ClN₂O (M+H)⁺: m/z=223.1. Found: 223.2.

Step 3.3-bromo-2-(1-chloroethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a stirred solution of2-(1-chloroethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.16 g, 14.2mmol) in methylene chloride (30 mL) was added drop-wise bromine (0.804mL, 15.6 mmol) in methylene chloride (7 mL). The reaction mixture wasstirred at room temperature for 2 h. The product precipitated out andwas collected by filtration (2.42 g, 56.6%). LCMS calculated forC₁₁H₁₁BrClN₂O (M+H)⁺: m/z=301.0. Found: 301.1.

Step 4.2-[1-(6-amino-9H-purin-9-yl)ethyl]-3-bromo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of3-bromo-2-(1-chloroethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.24g, 4.11 mmol), adenine (Sigma, 1.08 g, 8.04 mmol), and potassiumcarbonate (1.11 g, 8.04 mmol) in N,N-dimethylformamide (20 mL) wasstirred at room temperature overnight. The suspension was then pouredinto water and extracted with methylene chloride. The combined organiclayers were washed with water, brine, and then the organic layers driedand evaporated to dryness. The residue was chromatographed on silicagel, eluting with 0 to 10% MeOH in methylene chloride, to provide thedesired product (176 mg, 10.7%). LCMS calculated for C₁₆H₁₅BrN₇O (M+H)⁺:m/z=400.1. Found: 400.1. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.44 (1H, s), 8.07(1H, s), 7.67 (1H, dd, J=8.7 and 7.2 Hz), 7.30 (1H, br d, J=8.7 Hz),7.20 (2H, s), 6.99 (1H, br d, J=7.2 Hz), 6.15 (1H, q, J=7.2 Hz), 2.91(3H, s), 1.84 (3H, d, J=7.2 Hz) ppm.

Step 5.2-[1-(6-amino-9H-purin-9-yl)ethyl]-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a mixture of2-[1-(6-amino-9H-purin-9-yl)ethyl]-3-bromo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(0.030 g, 0.075 mmol) and phenylboronic acid (11.0 mg, 0.0899 mmol) in1,4-dioxane (0.6 mL) was added a 1 M solution of sodium carbonate (9.53mg, 0.0899 mmol) in water (0.089 mL) andtetrakis(triphenylphosphine)palladium (0) (4.33 mg, 0.00375 mmol). Thereaction mixture was heated at 100° C. overnight. After cooling to rt,the mixture was diluted with EtOAc, washed with water, brine, dried overMgSO₄, and concentrated. The residue was purified on RP-HPLC at pH 10(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.15% NH₄OH) to provide the desired product. LCMS calculatedfor C₂₂H₂₀N₇O (M+H)⁺: m/z=398.2. Found: 398.3. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.37 (1H, s), 7.97 (1H, s), 7.56 (1H, dd, J=8.7 and 6.6 Hz), 7.41-7.36(5H, m), 7.26 (1H, br d, J=9.0 Hz), 7.09 (2H, br s), 6.85 (1H, br d,J=7.2 Hz), 5.59 (1H, q, J=7.2 Hz), 2.80 (3H, s), 1.64 (3H, d, J=7.2 Hz)ppm.

Example 26-methyl-3-phenyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one

Step 1. methyl 4-bromo-3-oxohexanoate

Under a nitrogen atmosphere, a solution of bromine (8.61 mL, 167 mmol)in chloroform (20 mL) was added drop-wise over a period of 2 h to asolution of methyl 3-oxohexanoate (Fluka, 24.1 g, 167 mmol) inchloroform (147 mL), at 0° C. (ice bath). The reaction mixture wasstirred for 30 min at 0° C. and then allowed to warm to room temperatureovernight. While stirring, a stream of air was bubbled through thesolution for 1 hour. The reaction mixture was dried over sodium sulfateand the solvent evaporated under reduced pressure to provide the desiredcompound.

Step 2. 2-(1-bromopropyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a manually stirred polyphosphoric acid (80 g, 800 mmol) in a 1000 mLbeaker at room temperature was added 6-methyl-2-pyridinamine (15 g, 140mmol), followed by methyl 4-bromo-3-oxohexanoate (37.3 g, 167 mmol). Themixture was heated with stirring at 110° C. for 5 h. After cooling, thedark slurry was transferred into 300 g of ice. The pH of the mixture wasadjust to 6-7 with 10% sodium hydroxide. The precipitate was collectedby filtration under reduced pressure, washed with water, and air driedto yield the desired product (25.4 g, 64.8%). LCMS calculated forC₁₂H₁₄BrN₂O (M+H)⁺: m/z=281.0. Found: 281.2. ¹H NMR (DMSO-d₆, 300 MHz) δ7.66 (1H, d, J=9.0 and 6.9 Hz), 7.39 (1H, d, J=9.0 Hz), 6.90 (1H, d,J=6.9 Hz), 6.33 (1H, s), 4.91 (1H, t, J=7.5 Hz), 2.91 (3H, s), 2.15 (2H,qd, J=7.5 and 7.5 Hz), 0.93 (3H, t, J=7.5 Hz) ppm.

Step 3.2-(1-bromopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of 2-(1-bromopropyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(3.46 g, 12.3 mmol) and N-iodosuccinimide (4.15 g, 18.4 mmol) inacetonitrile (100 mL) was stirred at 80° C., under nitrogen, overnight.After removal of acetonitrile in vacuum, the resulting solid wasdissolved in methylene chloride, washed with water, saturated Na₂S₂O₃,saturated sodium bicarbonate, and brine; and then the organic layersdried over sodium sulfate and then filtered. The filtrate wasconcentrated under reduced pressure to provide the desired product (4.53g, 90.4%). LCMS calculated for C₁₂H₁₃BrIN₂O (M+H)⁺: m/z=406.9. Found:407.1.

Step 4.2-(1-azidopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of2-(1-bromopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (4.50g, 11.0 mmol) and sodium azide (3.59 g, 55.3 mmol) in DMF was stirred atroom temperature for 2 h. After diluting with ethyl acetate, the mixturewas washed with water, brine, dried over sodium sulfate, and evaporatedunder reduced pressure to provide the crude product, which was useddirectly in next step (3.35 g, 82.1%). LCMS calculated for C₁₂H₁₃IN₅O(M+H)⁺: m/z=370.0. Found: 370.2.

Step 5.2-(1-azidopropyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a mixture of2-(1-azidopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.11g, 0.29 mmol) and phenylboronic acid (42.9 mg, 0.352 mmol) in1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate (37.3mg, 0.352 mmol) in water (0.35 mL) andtetrakis(triphenylphosphine)palladium (0) (16.9 mg, 0.0147 mmol). Thereaction mixture was heated at 100° C. overnight. After cooling to rt,the mixture was diluted with EtOAc, washed with water, brine, dried overMgSO₄, and concentrated. The residue was purified on silica gel, elutingwith 0 to 40% EtOAc in hexane, to provide the desired product (50 mg,53.4%). LCMS calculated for C₁₈H₁₈N₅O (M+H)⁺: m/z=320.2. Found: 320.3.

Step 6.2-(1-aminopropyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a stirred solution of2-(1-azidopropyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one(0.030 g, 0.094 mmol) in tetrahydrofuran (0.24 mL) and water (0.06 mL)was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.11 mL) atroom temperature and the mixture was stirred at room temperature for 1hour. To the mixture was added methylene chloride and the mixture waswashed with brine, dried over magnesium sulfate, and evaporated todryness under reduced pressure. The crude residue was used directly innext step. LCMS calculated for C₁₈H₂₀N₃O (M+H)⁺: m/z=294.2. Found:294.3.

Step 7.6-methyl-3-phenyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of 6-bromo-9H-purine (Aldrich, 0.0152 g, 0.07656 mmol),2-(1-aminopropyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one(0.019 g, 0.064 mmol), and N,N-diisopropylethylamine (0.0134 mL, 0.07666mmol) in ethanol (0.5 mL) was refluxed under nitrogen overnight. Themixture was cooled and purified on RP-HPLC at pH 10 (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.15% NH₄OH) toprovide the product as the free base. LCMS calculated for C₂₃H₂₂N₇O(M+H)⁺: m/z=412.2. Found: 412.4. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.07 (2H,m), 7.60 (1H, dd, J=9.0 and 6.9 Hz), 7.39-7.32 (7H, m), 7.00 (1H, m),6.85 (1H, br d, J=6.9 Hz), 5.13 (1H, m), 2.81 (3H, s), 1.72 (2H, m),0.65 (3H, t, J=7.2 Hz) ppm.

Example 33-(5-fluoropyridin-3-yl)-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one

Step 1.2-(1-aminopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a stirred solution of2-(1-azidopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.10g, 8.40 mmol) in tetrahydrofuran (20 mL) and water (6.06 mL) was added a1.0 M solution of trimethylphosphine in tetrahydrofuran (0.1 mmol) atroom temperature and stirred for 1 hour. To the mixture was added EtOAcand the mixture was extracted twice with 1 N HCl. The combined extractswere neutralized with solid sodium bicarbonate and extracted withmethylene chloride. The combined organic layers were washed with brine,dried over magnesium sulfate, and concentrated under reduced pressure.The residue was used directly in next step (2.58 g, 89.5%). LCMScalculated for C₁₂H₁₅IN₃O (M+H)⁺: m/z=344.0. Found: 344.2.

Step 2.3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of 6-bromo-9H-purine (1.65 g, 0.008270 mol),2-(1-aminopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.58g, 0.00752 mol), and N,N-diisopropylethylamine (1.571 mL, 0.009022 mol)in ethanol (60 mL) was refluxed under nitrogen overnight. The mixturewas concentrated and the resulting residue was purified on silica gel,eluting with 0 to 10% methanol in methylene chloride, to provide thedesired product (2.86 g, 82.5%). LCMS calculated for C₁₇H₁₇IN₇O (M+H)⁺:m/z=462.1. Found: 462.2. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.31 (2H, m), 8.19(1H, s), 8.15 (1H, s), 7.69 (1H, dd, J=8.7 and 6.9 Hz), 7.44 (1H, d,J=8.7 Hz), 6.99 (1H, d, J=6.9 Hz), 5.69 (1H, m), 2.89 (3H, s), 1.91 (2H,m), 0.95 (3H, t, J=7.2 Hz) ppm.

Step 3.3-(5-fluoropyridin-3-yl)-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one

To a mixture of3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one(0.030 g, 0.065 mmol) and (5-fluoropyridin-3-yl)boronic acid(Combi-Blocks, 11.0 mg, 0.0780 mmol) in 1,4-dioxane (0.5 mL) was added a1 M solution of sodium carbonate (8.27 mg, 0.0780 mmol) in water (0.077mL) and tetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325mmol). The reaction mixture was heated at 100° C. overnight. Aftercooling to rt, the mixture was diluted with EtOAc, washed with water,brine, dried over MgSO₄, and concentrated. The residue was purified onRP-HPLC at pH 10 conditions (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.15% NH₄OH) to provide the desiredproduct. LCMS calculated for C₂₂H₂₀FN₈O (M+H)⁺: m/z=431.2. Found: 431.3.

Example 43-(3-fluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one

To a mixture of3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one(from example 3, step 2; 0.030 g, 0.065 mmol) and(3-fluorophenyl)boronic acid (Aldrich, 10.9 mg, 0.0780 mmol) in1,4-dioxane (0.5 mL) was added a 1 M solution of sodium carbonate (8.27mg, 0.0780 mmol) in water (0.077 mL) andtetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325 mmol). Thereaction mixture was heated at 100° C. overnight. After cooling to rt,the mixture was diluted with EtOAc, washed with water, brine, dried overMgSO₄, and concentrated. The residue was purified on RP-HPLC at pH 10conditions (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.15% NH₄OH) to provide the desiredproduct. LCMS calculated for C₂₃H₂₁FN₇O (M+H)⁺: m/z=430.2. Found: 430.3.¹H NMR (DMSO-d₆, 300 MHz) δ 8.11 (2H, m), 7.65 (1H, m), 7.45 (2H, m),7.24 (4H, m), 7.08 (1H, m), 6.91 (1H, m), 5.17 (1H, m), 2.87 (3H, s),1.79 (2H, m), 0.72 ((3H, t, J=7.2 Hz) ppm. ¹⁹F NMR (DMSO-d₆, 282 MHz) δ−114 ppm.

Example 53-(3,5-difluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one

To a mixture of3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one(from example 3, step 2; 0.030 g, 0.065 mmol) and(3,5-difluorophenyl)boronic acid (Aldrich, 12.3 mg, 0.0780 mmol) in1,4-dioxane (0.5 mL) was added a 1 M solution of sodium carbonate (8.27mg, 0.0780 mmol) in water (0.077 mL) andtetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325 mmol). Thereaction mixture was heated at 100° C. overnight. After cooling to rt,the mixture was diluted with EtOAc, washed with water, brine, dried overMgSO₄, and concentrated. The residue was purified on RP-HPLC at pH 10conditions (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.15% NH₄OH) to provide the desiredproduct. LCMS calculated for C₂₃H₂₀F₂N₇O (M+H)⁺: m/z=448.2. Found:448.3. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.06 (2H, m), 7.61 (1H, m), 7.38 (1H,m), 7.14 (5H, m), 6.88 (1H, m), 5.08 (1H, m), 2.83 (3H, s), 1.75 (2H,m), 0.70 ((3H, t, J=7.8 Hz) ppm. ¹⁹F NMR (DMSO-d₆, 282 MHz) δ −111 ppm.

Example 63-(2-fluoropyridin-3-yl)-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one

To a mixture of3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one(from example 3, step 2; 0.030 g, 0.065 mmol) and(2-fluoropyridin-3-yl)boronic acid (Alfa Aesar, 11.0 mg, 0.0780 mmol) in1,4-dioxane (0.5 mL) was added a 1 M solution of sodium carbonate (8.27mg, 0.0780 mmol) in water (0.077 mL) andtetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325 mmol). Thereaction mixture was heated at 100° C. overnight. After cooling to rt,the mixture was diluted with EtOAc, washed with water, brine, dried overMgSO₄, and concentrated. The residue was purified on RP-HPLC at pH 2conditions (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA) to provide the desired productas a TFA salt. LCMS calculated for free base C₂₂H₂₀FN₈O (M+H)⁺:m/z=431.2. Found: 431.3.

Example 76-methyl-2-[1-(9H-purin-6-ylamino)propyl]-3-(1H-pyrazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

To a mixture of3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one(from example 3, step 2; 0.030 g, 0.065 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich,15.1 mg, 0.0780 mmol) in 1,4-dioxane (0.5 mL) was added a 1 M solutionof sodium carbonate (8.27 mg, 0.0780 mmol) in water (0.077 mL) andtetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325 mmol). Thereaction mixture was heated at 100° C. overnight. After cooling to rt,the mixture was diluted with EtOAc, washed with water, brine, dried overMgSO₄, and concentrated. The residue was purified on RP-HPLC at pH 2conditions (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA) to provide the desired productas a TFA salt. LCMS calculated for free base C₂₀H₂₀N₉O (M+H)⁺:m/z=402.2. Found: 402.1.

Example 83-methyl-6-phenyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1. methyl 4-bromo-3-oxopentanoate

Under a nitrogen atmosphere, a solution of bromine (8.61 mL, 167 mmol)in chloroform (20 mL, 200 mmol) was added dropwise over a period of 2 hto a solution of 3-oxopentanoic acid, methyl ester (Aldrich, 21.0 mL,167 mmol) in chloroform (147 mL, 1840 mmol), at 0° C. (ice bath). Thereaction mixture was stirred for 30 min at 0° C. and then allowed tostand at room temperature overnight. While stirring, a stream of air wasbubbled through the solution for 1 hour. After drying over sodiumsulfate, the solvent was evaporated under reduced pressure leaving thedesired compound.

Step 2. 7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a manually stirred polyphosphoric acid (80 g, 800 mmol) in a 1000 mLbeaker was added 4-methyl-1,3-thiazol-2-amine (Aldrich, 16 g, 140 mmol),followed by methyl 4-bromo-3-oxopentanoate (34.9 g, 167 mmol). Themixture was heated with stirring at 110° C. for 5 h. After cooling, thedark slurry was transferred into 300 g of ice. The pH of the mixture wasadjust to 6-7 with 10% sodium hydroxide. The aqueous layer was discardedand the dark oil layer was diluted with methylene chloride and washedwith 1 N NaOH, brine, dried over magnesium sulfate, and evaporated todryness to yield the desired product (16.2 g, 42.6%). LCMS calculatedfor C₉H₁₀BrN₂OS (M+H)⁺: m/z=273.0. Found: 273.1.

Step 2.6-bromo-7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (16.2g, 59.3 mmol) and N-bromosuccinimide (15.8 g, 89.0 mmol) in acetonitrile(500 mL) was stirred at 80° C., under nitrogen, overnight. After removalof acetonitrile in vacuum, the resulting solid was dissolved inmethylene chloride, washed with water, saturated Na₂S₂O₃, saturatedsodium bicarbonate, and brine; and then the organic layers dried oversodium sulfate and filtered. The filtrate was concentrated under reducedpressure to provide the desired product (19.5 g, 93.4%). LCMS calculatedfor C₉H₉Br₂N₂OS (M+H)⁺: m/z=350.9. Found: 351.0.

Step 3.7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 6-bromo-7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (11.1 g, 31.5mmol) and sodium azide (6.15 g, 94.6 mmol) in dimethyl formamide (DMF)(100 mL) was stirred at room temperature for 2 h. After diluting withEtOAc, the mixture was washed with water, brine, dried over sodiumsulfate, and evaporated under reduced pressure. The crude residue waspurified on silica gel, eluting with 0 to 80% EtOAc in hexane, toprovide the product (8.68 g, 87.6%). LCMS calculated for C₉H₉BrN₅OS(M+H)⁺: m/z=314.0. Found: 313.9. ¹H NMR (DMSO-d₆, 300 MHz) δ 7.15 (1H,s), 4.83 (1H, q, J=6.6 Hz), 2.69 (3H, s), 1.48 (3H, d, J=6.6 Hz) ppm.

Step 4.7-(1-azidoethyl)-3-methyl-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.100 g, 0.318 mmol) and phenylboronic acid (46.6 mg, 0.382 mmol) in1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate (40.5mg, 0.382 mmol) in water (0.38 mL) andtetrakis(triphenylphosphine)palladium (0) (18.4 mg, 0.0159 mmol). Thereaction mixture was heated at 100° C. overnight. After cooling to rt,the mixture was diluted with EtOAc, washed with water, brine, dried overMgSO₄, and concentrated. The residue was purified on silica gel, elutingwith 0 to 50% EtOAc in hexane, to provide the desired product (44 mg,44.4%). LCMS calculated for C₁₅H₁₄N₅OS (M+H)⁺: m/z=312.1. Found: 312.3.

Step 5.7-(1-aminoethyl)-3-methyl-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-3-methyl-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.044 g, 0.14 mmol) in tetrahydrofuran (0.4 mL) and water (0.102 mL)was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.17 mL) atroom temperature and the mixture was stirred at room temperature for 1hour. To the mixture was added EtOAc and the mixture was extracted twicewith 1 N HCl. The combined extracts were neutralized with solid sodiumbicarbonate and extracted with methylene chloride. The combined organiclayers were washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was used directly innext step (36 mg, 89.3%). LCMS calculated for C₁₅H₁₆N₃OS (M+H)⁺:m/z=286.1. Found: 286.0.

Step 6.3-methyl-6-phenyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 6-bromo-9H-purine (0.01504 g, 0.0076 mmol),7-(1-aminoethyl)-3-methyl-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.018 g, 0.063 mmol), and N,N-diisopropylethylamine (0.013 mL, 0.0076mol) in ethanol (0.5 mL) was refluxed under nitrogen overnight. Themixture was concentrated under reduced pressure and the residue waspurified on RP-HPLC at pH 2 to provide the product as a TFA salt. LCMScalculated for free base C₂₀H₁₈N₇OS (M+H)⁺: m/z=404.1. Found: 404.3. ¹HNMR (DMSO-d₆, 300 MHz) for a TFA salt: δ 8.54 (2H, m), 8.41 (2H, m),7.44-7.36 (5H, m), 7.08 (1H, d, J=1.2 Hz), 5.21 (1H, m), 2.64 (3H, s),1.38 (3H, d, J=6.6 Hz) ppm.

Example 97-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-3-methyl-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 2-amino-6-bromopurine (Aldrich, 0.01618 g, 0.007558 mmol),7-(1-aminoethyl)-3-methyl-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from example 8, step 5; 0.018 g, 0.063 mmol), andN,N-diisopropylethylamine (0.01318 mL, 0.007569 mmol) in ethanol (0.5mL) was refluxed under nitrogen overnight. The mixture was evaporatedand the resulting residue was purified on RP-HPLC at pH 2 to provide theproduct as a TFA salt. LCMS calculated for C₂₀H₁₉N₈OS (M+H)⁺: m/z=419.1.Found: 419.3. ¹H NMR (DMSO-d₆, 300 MHz) for TFA salt: δ 8.74 (1H, m),8.16 (1H, s), 7.46-7.33 (6H, m), 7.14-7.11 (3H, m), 5.20 (1H, m), 2.66(3H, d, J=1.5 Hz), 1.32 (3H, d, J=6.6 Hz) ppm.

Example 106-(3-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1.7-(1-azidoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from example 8, step 3; 0.100 g, 0.318 mmol) and(3-fluorophenyl)boronic acid (53.4 mg, 0.382 mmol) in 1,4-dioxane (2 mL)was added a 1 M solution of sodium carbonate (40.5 mg, 0.382 mmol) inwater (0.38 mL) and tetrakis(triphenylphosphine)palladium (0) (18.4 mg,0.0159 mmol). The reaction mixture was heated at 100° C. overnight.After cooling to rt, the mixture was diluted with EtOAc, washed withwater, brine, dried over MgSO₄, and concentrated. The residue waspurified on silica gel, eluting with 0 to 50% EtOAc in hexane, toprovide the desired product (35 mg, 33.4%). LCMS calculated forC₁₅H₁₃FN₅OS (M+H)⁺: m/z=330.1. Found: 330.2.

Step 2.7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.037 g, 0.11 mmol) in tetrahydrofuran (0.3 mL) and water (0.0811 mL)was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.13 mmol) atroom temperature and stirred for 1 hour. To the mixture was added EtOAcand was extracted twice with 1 N HCl. The combined extracts wereneutralized with solid sodium bicarbonate and extracted with methylenechloride. The combined organic layers were washed with brine, dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas used directly in next step (31 mg, 90.9%). LCMS calculated forC₁₅H₁₅FN₃OS (M+H)⁺: m/z=304.1. Found: 304.3.

Step 3.6-(3-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 6-bromo-9H-purine (0.01258 g, 0.006320 mmol),7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.016 g, 0.053 mmol), and N,N-diisopropylethylamine (0.011 mL, 0.006329mmol) in ethanol (0.4 mL) was refluxed under nitrogen overnight. Themixture was evaporated and the resulting residue was purified on RP-HPLCat pH 2 to provide the product as a TFA salt. LCMS calculated forC₂₀H₁₇FN₇OS (M+H)⁺: m/z=422.1. Found: 422.3. ¹H NMR (DMSO-d₆, 300 MHz)for TFA salt: δ 8.55 (2H, m), 8.40 (2H, m), 7.48 (1H, m), 7.25-7.22 (3H,m), 7.09 (1H, s), 5.19 (1H, m), 2.64 (3H, d, J=0.9 Hz), 1.40 (3H, d,J=6.6 Hz) ppm. ¹⁹F NMR (DMSO-d₆, 282 MHz) for TFA salt: δ −74.2, −114.0ppm.

Example 117-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 2-amino-6-bromopurine (0.01353 g, 0.006320 mmol),7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from example 10, step 2; 0.016 g, 0.053 mmol), andN,N-diisopropylethylamine (0.01102 mL, 0.006329 mmol) in ethanol (0.4mL) was refluxed under nitrogen overnight. The mixture was evaporatedand the resultant residue was purified on RP-HPLC at pH 2 to provide theproduct as a TFA salt. LCMS calculated for C₂₀H₁₈FN₈OS (M+H)⁺:m/z=437.1. Found: 437.3. ¹H NMR (DMSO-d₆, 300 MHz) for TFA salt: δ 8.74(1H, m), 8.16 (1H, s), 7.46 (1H, m), 7.20-7.13 (7H, m), 5.18 (1H, m),2.66 (3H, s), 1.33 (3H, d, J=6.9 Hz) ppm. ¹⁹F NMR (DMSO-d₆, 282 MHz) forTFA salt: δ −74.0, −114.0 ppm.

Example 126-(3,5-difluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1.7-(1-azidoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.10 g, 0.318 mmol) and (3,5-difluorophenyl)boronic acid (60.3 mg,0.382 mmol) in 1,4-dioxane (2 mL) was added a 1 M solution of sodiumcarbonate (40.5 mg, 0.382 mmol) in water (0.38 mL) andtetrakis(triphenylphosphine)palladium (0) (18.4 mg, 0.0159 mmol). Thereaction mixture was heated at 100° C. overnight. After cooling to rt,the mixture was diluted with EtOAc, washed with water, brine, dried overMgSO4, and concentrated. The residue was purified on silica gel, elutingwith 0 to 40% EtOAc in hexane, to provide the desired product (42 mg,38.0%). LCMS calculated for C₁₅H₁₂F₂N₅OS (M+H)⁺: m/z=348.1. Found:348.2.

Step 2.7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.042 g, 0.12 mmol) in tetrahydrofuran (0.3 mL) and water (0.0873 mL)was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.14 mmol) atroom temperature and stirred for 1 hour. To the mixture was added EtOAcand the mixture was extracted twice with 1 N HCl. The combined extractswere neutralized with solid sodium bicarbonate, and extracted withmethylene chloride. The combined organic layers were washed with brine,dried over magnesium sulfate, and concentrated under reduced pressure.The residue was used directly in next step (36 mg, 92.7%). LCMScalculated for C₁₅H₁₄F₂N₃OS (M+H)⁺: m/z=322.1. Found: 322.3.

Step 3.6-(3,5-difluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 6-bromo-9H-purine (0.01258 g, 0.006320 mmol),7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.017 g, 0.053 mmol), and N,N-diisopropylethylamine (0.011 mL, 0.006329mmol) in ethanol (0.4 mL) was refluxed under nitrogen overnight. Themixture was concentrated under reduced pressure and the resultantresidue was purified on RP-HPLC at pH 2 to provide the product as a TFAsalt. LCMS calculated for C₂₀H₁₆F₂N₇OS (M+H)⁺: m/z=440.1. Found: 440.3.¹H NMR (DMSO-d₆, 300 MHz) for TFA salt: δ 8.55 (1H, m), 8.39 (2H, m),7.29 (1H, m), 7.15-7.11 (3H, m), 5.17 (1H, m), 2.64 (3H, d, J=1.2 Hz),1.42 (3H, d, J=6.9 Hz) ppm.

Example 137-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 2-amino-6-bromopurine (0.01436 g, 0.006712 mmol),7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from example 12, step 2; 0.018 g, 0.056 mmol), andN,N-diisopropylethylamine (0.01171 mL, 0.006722 mmol) in ethanol (0.4mL) was refluxed under nitrogen overnight. The mixture was evaporatedand the resultant residue was purified on RP-HPLC at pH 2 to provide theproduct as a TFA salt. LCMS calculated for C₂₀H₁₇F₂N₈OS (M+H)⁺:m/z=455.1. Found: 455.3. ¹H NMR (DMSO-d₆, 300 MHz) for TFA salt: δ 8.74(1H, m), 8.16 (1H, s), 7.26-7.06 (6H, m), 5.16 (1H, m), 2.66 (3H, d,J=1.2 Hz), 1.36 (3H, d, J=6.9 Hz) ppm.

Example 143-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1.7-(1-azidoethyl)-3-methyl-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 2-(tributylstannyl)pyridine (Aldrich, 0.176 g, 0.382 mmol),7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(from example 8, step 3; 0.10 g, 0.318 mmol), andtetrakis(triphenylphosphine)palladium (0) (0.0184 g, 0.0159 mmol) in1,4-dioxane (0.5 mL) was heated at 65° C. overnight. After being cooledand quenched with saturated ammonium chloride, the resulting mixture wasextracted with EtOAc. The organic layers were combined, washed withbrine, dried and evaporated to dryness. The residue was purified onsilica gel, eluting with 0 to 100% EtOAc in hexane, to provide thedesired product (13 mg, 13%). LCMS calculated for C₁₄H₁₃N₆OS (M+H)⁺:m/z=313.1. Found: 313.0.

Step 2.7-(1-aminoethyl)-3-methyl-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-3-methyl-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.012 g, 0.039 mmol) in tetrahydrofuran (0.1 mL) and water (0.0285 mL)was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.047 mmol) atroom temperature and stirred for 1 hour. To the mixture was added EtOAcand the mixture was extracted twice with 1 N HCl. The combined extractswere neutralized with solid sodium bicarbonate and extracted withmethylene chloride. The combined organic layers were washed with brine,dried over magnesium sulfate, and concentrated under reduced pressure.The residue was used directly in next step. LCMS calculated forC₁₄H₁₅N₄OS (M+H)⁺: m/z=287.1. Found: 287.0.

Step 3.3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 6-bromo-9H-purine (9.300 mg, 0.004673 mmol),7-(1-aminoethyl)-3-methyl-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(11 mg, 0.039 mmol), and N,N-diisopropylethylamine (8.152 μL, 0.004680mmol) in ethanol (0.3 mL) was refluxed under nitrogen overnight. Themixture was concentrated under reduced pressure and the residue waspurified on RP-HPLC (eluting with a gradient of methanol/watercontaining 1% TFA) to provide the product as a TFA salt. LCMS calculatedfor C₁₉H₁₇N₈OS (M+H)⁺: m/z=405.1. Found: 405.3.

Example 15(S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Step 1. 7-(1-Bromoethyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

A solution of 3-oxopentanoic acid methyl ester (12.5 g, 96.0 mmol) inmethylene chloride (50 mL) was cooled with an ice water bath. The outletof the flask was attached to a NaOH trap. Bromine (5.19 mL, 101 mmol) inmethylene chloride (10 mL, 200 mmol) was added dropwise over a 20-minperiod, and the reaction mixture was allowed to warm to room temperatureand then stirred overnight. The reaction mixture was bubbled withnitrogen for 30 min and then concentrated to give an oil. This oil wasused in the next step without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 4.89 (q, J=6.9 Hz, 1H), 3.85 (s, 2H), 3.63 (s, 3H), 1.64 (d,J=6.7 Hz, 3H).

Into a 3-neck flask fitted with a condenser, a thermometer, and anitrogen inlet was added polyphosphoric acid (50.0 g, 458 mmol). Theflask was heated to 70° C. to give a liquid that was easy to stir.4-Methyl-1,3-thiazol-2-amine (10.0 g, 87.6 mmol) was added in smallportions with stirring. The internal temperature slowly increased to 78°C. upon mixing. The crude oil obtained above was then added to the flaskvia a pipette and the mixture was heated to 110° C. under nitrogen.After 6 h of heating, HPLC indicated that the reaction was complete.

The reaction mixture was cooled to ˜35° C. Water (70 mL) and EtOAc (200mL) were added. The mixture was stirred until all solids dissolved. Theorganic layer was separated. The aqueous layer was extracted with EtOAc(200 mL×2). The combined organic extracts were washed with 1 N aqueousHCl (40 mL×2) with sat. NaHCO₃ (50 mL×2) and brine (30 mL). The organiclayer was dried and concentrated to give7-(1-bromoethyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one as a yellowsolid (11.8 g, 49.3%). LCMS calculated for C₉H₁₀BrN₂OS (M+H)⁺: m/z274.96, 272.96. Found: 274.75, 272.75. ¹H NMR (400 MHz, DMSO-d₆) δ 7.05(m, 1H), 6.27 (s, 1H), 5.17 (q, J=6.9 Hz, 1H), 2.65 (s, 3H), 1.85 (d,J=6.9 Hz, 3H).

Step 2.6-Bromo-7-(1-bromoethyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

Under nitrogen, a suspension of7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (13.2g, 48.3 mmol) in acetonitrile (100 mL, 2000 mmol) was stirred until aclear solution was obtained. N-Bromosuccinimide (9.891 g, 55.57 mmol)was then added and the reaction mixture was stirred at 50° C. After 20min, HPLC indicated that the reaction was complete. A solution of sodiumsulfite (3.046 g, 24.16 mmol) in water (50 mL) was added and the mixturewas stirred at room temperature for 20 min. Water (200 mL) was addedslowly and the mixture stirred at room temperature for 30 min. and thenfiltered. The solid was washed with water (100 mL×3) and dried to give6-bromo-7-(1-bromoethyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one asan off-white solid (15.61 g, 91%). LCMS calculated for C₉H₉Br₂N₂OS(M+H)⁺: m/z 352.87, 354.87. Found: 352.65, 354.60. ¹H NMR (400 MHz,DMSO-d₆) δ 7.15 (q, J=1.3 Hz, 1H), 5.51 (q, J=6.7 Hz, 1H), 2.66 (d,J=1.2 Hz, 3H), 1.90 (d, J=6.7 Hz, 3H).

Step 3.7-(1-Azidoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

To a suspension of6-bromo-7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(6.85 g, 19.4 mmol) in N,N-dimethylformamide (30.1 mL) was added sodiumazide (1.45 g, 22.4 mmol). The mixture slowly turned clear after 5-10min. After 50 min, a solution of sodium bicarbonate (4.7 g, 56 mmol) inwater (90 mL) was added dropwise with stirring. The mixture was stirredat room temperature for 1 h and the solid precipitates were filteredoff. The solid was then washed with water (30 mL×3), and dried to give7-(1-azidoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one asan off-white solid (5.94 g, 97.2%). LCMS calculated for C₉H₉BrN₅OS(M+H)⁺: m/z 313.96, 315.96. Found: 313.75, 315.75. ¹H NMR (400 MHz,DMSO-d₆) δ 7.15 (q, J=1.3 Hz, 1H), 4.83 (q, J=6.8 Hz, 1H), 2.67 (d,J=1.4 Hz, 3H), 1.48 (d, J=6.8 Hz, 3H).

Step 4.7-(1-Aminoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

7-(1-Azidoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(22.6 g, 71.9 mmol) was mixed with methanol (200 mL). Sodium iodide(64.7 g, 432 mmol) was added and stirred at room temperature for 10 min.Chlorotrimethylsilane (54.8 mL, 432 mmol) was dissolved in methanol(29.1 mL) and added dropwise over 10 min. at 5-25° C. The reactionmixture was stirred at room temperature for 10 min. HPLC and TLC showedthat the reaction was complete. The reaction was quenched by addition ofa solution of sodium thiosulfate (69.4 g, 439 mmol) in water (259 ml)while maintaining the batch temperature at 5-25° C. A large amount ofsolid was formed, and the pH of the mixture was 3. The mixture wasstirred at 0-5° C. for 30 min. The pH was adjusted to 11 using 3 Naqueous sodium hydroxide (85 mL). In order to facilitate productpurification and isolation, the N-Boc derivative of the product wasprepared. To the mixture was added di-t-butyldicarbonate (28.3 g, 129mmol) and the reaction mixture was stirred at room temperature for 2 h.HPLC indicated a small amount of amine remained unreacted. Additionaldi-t-butyldicarbonate (10.0 g, 45.8 mmol) was added followed by 3 Naqueous sodium hydroxide (15 mL) to adjust the pH to 11. The reactionmixture was stirred at room temperature for 30 min. The reaction mixturewas extracted with ethyl acetate (150 mL×3). The organic solution whichcontained the N-Boc derivative of the product was dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure togive a residue. The residue was added to a 4 M solution of hydrogenchloride in 1,4-dioxane (206 mL, 824 mmol) and stirred at roomtemperature for 1.5 h. HPLC indicated the N-Boc-deprotection wascomplete. The hydrochloride salt of the product was isolated byfiltration, the solid washed with MTBE, dried by suction filtration for1 h to give7-(1-aminoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onehydrochloride salt (25.1 g) as a purple powder.

The hydrochloride salt was dissolved in water (50 mL) and a 50% solutionof sodium hydroxide (about 5 mL) was added to adjust the pH to 11. Themixture was stirred at room temperature for 20 min. The productprecipitated and was isolated by filtration. The wet solid was washedwith water (10 mL) and dried on the filter under vacuum for 18 h to give7-(1-aminoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(18.8 g, 65.2 mmol, 90.7% yield) as a yellow powder. LCMS calculated forC₉H₁₁BrN₃OS (M+H)⁺: m/z 287.97, 289.97. Found: 287.75, 289.75. ¹H NMR(400 MHz, DMSO-d₆) 7.08 (q, J=1.3 Hz, 1H), 4.19 (q, J=6.7 Hz, 1H), 2.65(d, J=1.3 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H).

Step 5.(S)-1-(6-bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethanaminium(S)-2-hydroxy-2-phenylacetate

7-(1-Aminoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(18.8 g, 65.2 mmol) was dissolved in isopropanol (375 mL) at reflux andthen (S)-(+)-mandelic acid (4.84 g, 31.8 mmol) in isopropanol (375 mL)was added dropwise to the amine solution over 35 min. The reactionmixture was allowed to cool to about 72° C. and solid precipitation wasobserved. The slurry was cooled to room temperature and stirred for 1hour. The solid product was collected by filtration. The wet cake waswashed with isopropanol (100 mL) and dried on the filter under suctionfor 1 h to give the product(S)-1-(6-bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethanaminium(S)-2-hydroxy-2-phenylacetate (11.9 g) as a white solid. Chiral HPLCanalysis was performed on a Lux Cellulose-2, 4.6×250 mm, 5 micron columnusing 60% ethanol/40% hexanes as the mobile phase at a flow rate of 1mL/min. The major enantiomer eluted at retention time 11.21 min (99.0area %). The minor enantiomer eluted at retention time 14.31 min (0.96area %). The e.e. of the desired product was 98.08%.

The product at 98.08% e.e. (11.9 g) was suspended in isopropanol (750mL) and heated under reflux for 30 min. The slurry was cooled to roomtemperature with stirring. The solid was collected by filtration. Thewet solid was washed with isopropanol (100 mL) and dried on the filterunder suction for 18 h to give 10.9 g of white solid. Chiral HPLC by themethod described above gave e.e. of 98.48%.

The product at 98.48% e.e. (10.9 g) was stirred in a solution of sodiumcarbonate (3.9 g, 37 mmol) in water (100 mL) at room temperature for 30min. The solid free base was collected by filtration, washed with water(20 mL) and dried on the filter under suction for 2 h to give a slightlywet cake (13 g). The wet solid was dissolved in isopropanol (325 mL) atreflux and a solution of (S)-(+)-mandelic acid (3.613 g, 23.75 mmol) inisopropanol (325 mL) was added dropwise over 20 min to the free basesolution. The solution was cooled to room temperature with stirring. Thesolid product was collected by filtration, washed with isopropanol (100mL) and dried on the filter under suction for 48 h to give pure product(S)-1-(6-bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethanaminium(S)-2-hydroxy-2-phenylacetate (8.4 g, 19.08 mmol, 29.3% yield) as awhite solid. The e.e. of this sample was determined to be 100% as nominor enantiomer (retention time=14.31 min) was detected. LCMScalculated for C₉H₁₁BrN₃OS (M+H)′ for the free base: m/z 289.97, 287.97.Found: 289.75, 287.75. ¹H NMR (400 MHz, DMSO-d₆) δ 7.33 (d, J=7.5 Hz,2H), 7.22 (dd, J=7.1, 7.5 Hz, 2H), 7.16 (m, 2H), 4.61 (s, 1H), 4.47 (q,J=6.9 Hz, 1H), 2.68 (d, J=1.1 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H).

In order to determine the absolute stereochemistry of the product, asample was sublimed at about 105° C. to provide colorless needlessuitable for X-ray crystal structure analysis. The study determined theabsolute configuration of the amine bearing carbon (C-8) is S (seeExample 16 and FIG. 1).

Step 6. (S)-tert-Butyl1-(6-(3-fluorophenyl)-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate

(S)-1-(6-Bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethanaminium(S)-2-hydroxy-2-phenylacetate (4.93 g, 11.2 mmol) was dissolved in THF(100 mL) and water (33 mL). Di-t-butyldicarbonate (3.03 g, 13.9 mmol)was added, followed by sodium bicarbonate (1.88 g, 22.4 mmol). Thereaction mixture was stirred at room temperature for 30 min. at whichpoint the HPLC showed the reaction was near complete. Additionaldi-t-butyldicarbonate (0.49 g, 2.24 mmol) was then added and thereaction mixture was stirred at room temperature for 1 hour. Thereaction was shown to be complete by HPLC. The reaction mixture wasdiluted with water (100 mL) and extracted with ethyl acetate (2×100 mL).The ethyl acetate solution was concentrated to give (S)-tert-butyl1-(6-bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate(5.46 g, 14.1 mmol, 126% yield) which was used in the subsequent Suzukicoupling reaction without further purification.

(S)-tert-Butyl1-(6-bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate(5.46 g, 14.1 mmol) and (3-fluorophenyl)boronic acid (2.95 g, 21.1 mmol)were suspected in 1,4-dioxane (110 mL). A solution of sodium carbonate(4.47 g, 42.2 mmol) in water (27 mL) was added to the mixture followedby tetrakis(triphenylphosphine)palladium(0) catalyst (0.81 g, 0.70mmol). The reaction mixture was degassed and heated under nitrogen at100° C. for 16 h. HPLC indicated the starting material was consumed. Thereaction mixture was cooled to room temperature and water (100 mL) wasadded. The resultant mixture was extracted with ethyl acetate (2×100mL). The ethyl acetate solution was washed with saturated aqueous sodiumbicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to give a residue. The residue waspurified by flash column chromatography on silica gel using 1-50% ethylacetate in hexane as eluent to give (S)-tert-butyl1-(6-(3-fluorophenyl)-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate(4.34 g, 10.8 mmol, 76%) as an off-white solid. LCMS calculated forC₂₀H₂₃FN₃O₃S (M+H)⁺: m/z 404.1. Found 404.1. ¹H NMR (500 MHz, DMSO-d₆) δ7.48 (ddd, J=8.1, 7.8, 6.2 Hz, 1H), 7.18 (m, 3H), 7.05 (q, J=1.3 Hz,1H), 6.96 (d, J=7.5 Hz, 1H), 4.41 (m, 1H), 2.66 (d, J=1.3 Hz, 3H), 1.33(s, 9H), 1.13 (d, J=6.8 Hz, 3H).

Step 7.(S)-7-(1-Aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

(S)-tert-Butyl1-(6-(3-fluorophenyl)-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate(4.15 g, 10.3 mmol) was dissolved in a 4.0 M solution of hydrogenchloride in 1,4-dioxane (25.7 mL, 102.8 mmol) and the solution wasstirred at room temperature for 45 min. HPLC indicated that the reactionwas complete. To the solution was added water (10 mL) followed by 3 Naqueous sodium hydroxide solution at 0-5° C. to adjust the pH to 10. Theaqueous mixture was extracted with ethyl acetate (2×30 mL). The ethylacetate solution was dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to give(S)-7-(1-Aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(3.30 g, 10.88 mmol, 103% yield). LCMS calculated for C₁₅H₁₅FN₃OS(M+H)⁺: m/z 304.08. Found 303.9. ¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (ddd,J=8.1, 7.9, 5.9 Hz, 1H), 7.19 (m, 1H), 7.12 (m, 2H) 7.04 (q, J=1.1 Hz,1H), 3.57 (q, J=6.6 Hz, 1H), 2.64 (d, J=1.3 Hz, 3H), 1.10 (d, J=6.7 Hz,3H)

Step 8.(S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

(S)-7-(1-Aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(2.30 g, 7.58 mmol), 6-bromo-9H-purine (2.716 g, 13.65 mmol),N,N-diisopropylethylamine (6.60 mL, 37.9 mmol) were dissolved in ethanol(15 mL) and the resultant mixture was heated at reflux under a nitrogenatmosphere for 17 h. HPLC indicated the reaction was complete. Thereaction mixture was concentrated under reduced pressure to give aresidue. The residue was purified by flash column chromatography onsilica gel using gradient elution starting at 100% DCM with increasingpolarity to 25% of a mixture of DCM/MeOH/aq.NH₄OH (100:5:0.5, v/v/v) inDCM. After the silica chromatography, 2.1 g of crude product wasobtained. This crude product was further purified by preparativereversed phase HPLC using 0.1% TFA in water and acetonitrile as mobilephases at a flow rate of 60 mL/min. on a SunFire C18, 5 μM, 30×100 mmcolumn. Pure(S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt (trifluoroacetic acid salt) (1.86 g, 3.47mmol, 45.8% yield) was obtained as a white solid after lyophilization.LCMS calculated for C₂₀H₁₇FN₇OS (M+H)⁺ for the free base: m/z 422.1.Found: 422.0). ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (br s, 1H), 8.53 (s,1H), 8.51 (s, 1H), 7.47 (m, 1H), 7.21 (m, 3H), 7.09 (s, 1H), 5.23 (m,1H), 2.65 (d, J=1.3 Hz, 3H), 1.43 (d, J=7.0 Hz, 3H). ¹³C NMR (125 MHz,DMSO-d₆) δ 164.0, 162.1 (J_(CF)=244.9 Hz), 160.5, 160.3, 150.9, 147.6,147.5, 144.4, 135.9, 135.9, 130.2 (J_(CF)=8.3 Hz), 126.9, 117.4(J_(cf)=22.6 Hz), 116.1, 114.8 (J_(CF)=21.5 Hz), 111.1, 107.8, 48.5,19.6, 18.0. Reversed phase analytical HPLC showed purity at 99.8 area %.Chiral HPLC analysis was performed on Chiralcel OJ-H, 4.6×250 mm, 5micron column using 60% ethanol/40% hexanes as eluent at a flow rate of0.5 mL/min. The peak for the desired enantiomer(S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onewas observed at a retention time of 21.171 min. (99.1 area %). The minorpeak for the undesired enantiomer(R)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onewas observed at a retention time of 13.358 min (0.9 area %). Theenantiomeric excess of the desired enantiomer was 98.2%.

Example 15A(S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one

A mixture of(S)-7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(108.2 g, 357 mmol), 6-chloropurine (71.73 g, 464.1 mmol), andN,N-diisopropylethylamine (74.6 mL, 428.4 mmol) in 1-butanol (952 mL)was degassed with nitrogen bubbling for 5 minutes. The reaction mixturewas heated at 105° C. under nitrogen for 15 hours, at which point HPLCindicated amine was consumed. The reaction mixture was cooled down toroom temperature before being treated with water (200 mL) at roomtemperature. The resulting mixture was concentrated under reducedpressure to give an oily residue and the residue was treated with CH₂Cl₂(1000 mL) to give a brownish clear solution. The resulting solution waswashed with 2.5% aqueous sodium carbonate solution (Na₂CO₃, 250 mL×2)and the organic layer was concentrated under reduced pressure to affordthe crude desired product as a brownish solid. The solution of the crudedesired product in CH₂Cl₂ was absorbed onto silica gel (300 g) and thedried silica gel was loaded onto a flash column. The flash column waseluted with pure CH₂Cl₂ and a mixture of CH₂Cl₂, MeOH and aqueous NH₄OH(2000:10:5) to afford pure desired product. The fractions containingpure desired product were combined and concentrated under reducedpressure. The resulting yellowish solid (90.3 g) was dissolved in amixture of CH₂Cl₂ and methanol (500:50 mL). The resulting solution wastreated with ethyl acetate (900 mL) and the resulting mixture wasdistilled until the internal solution temperature reached 68° C. Themixture was then cooled to room temperature and subsequently to 0-5° C.for 1 hour. The solids were collected by filtration, washed with coldethyl acetate (100 mL), and dried overnight on the filter under vacuumto afford(S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one(89.5 g, 59.4% yield, 99.4% ee) as a light yellowish solid. LCMScalculated for C₂₀H₁₇FN₇OS (M+H)⁺ for the free base: m/z 422.1. Found:422.0; ¹H NMR (500 MHz, DMSO-d₆) δ 8.40 (s, 1H), 7.99 (br s, 1H), 7.45(m, 1H), 7.21-7.12 (m, 3H), 6.8 (m, 1H), 6.42 (s, 1H), 5.52 (br s, 1H),2.79 (d, J=1.3 Hz, 3H), 1.43 (d, J=7.0 Hz, 3H).

Example 16 X-Ray Crystallography of(S)-1-(6-bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethanaminium(S)-2-hydroxy-2-phenylacetate (From Example 15, Step 5)

In order to determine the absolute stereochemistry of the product fromExample 15, step 5, a sample was sublimed at about 105° C. to providecolorless needles suitable for X-ray crystal structure analysis. Thestudy determined the absolute configuration of the amine bearing carbon(C-8) is S.

Data Collection:

Bruker SMART APEX-II CCD system, MoKalpha radiation, standard focustube, anode power=50 kV×42 mA, crystal to plate distance=5.0 cm, 512×512pixels/frame, beam center=(256.13, 253.14), total frames=1081,oscillation/frame=0.50°, exposure/frame=300.1 sec/frame, SAINTintegration, hid min/max=(−4, 7, −14, 14, −31, 35), data input toshelx=11285, unique data=3870, two-theta range=3.82 to 53.64°,completeness to two-theta 53.64=99.70%, R(int-xl)=0.0908, SADABScorrection applied.

Solution and Refinement:

Structure solved using XS(Shelxtl), refined using shelxtl softwarepackage, refinement by full-matrix least squares on F², scatteringfactors from Int. Tab. Vol C Tables 4.2.6.8 and 6.1.1.4, number ofdata=3870, number of restraints=0, number of parameters=309,data/parameter ratio=12.52, goodness-of-fit on F²=0.99, Rindices[I>4sigma(I)] R1=0.0455, wR2=0.0674, R indices (all data)R1=0.1059, wR2=0.0825, max difference peak and hole=0.420 and −0.863e/Å³, refined flack parameter=0.025(11). All of the hydrogen atoms havebeen found from a difference map and fully refined.

Crystal Data:

C17 H18 Br N3 O4 S, from sublimation @ 105° C., colorless, needle,˜0.160×0.020×0.020 mm, orthorhombic, P212121, a=5.5572(18) Å,b=11.547(4) Å, c=28.207(10) Å, Vol=1810.1(11) Å³, Z=4, T=−100° C.,Formula weight=440.31, Density=1.616 g/cm³, μ(Mo)=2.41 mm⁻¹.

Results:

This study determined the structure of C17, H18, N3, O4, S1, Br1 for theproduct of Example 15, step 5. The asymmetric unit contains one of eachmolecule as shown in FIG. 1 with thermal ellipsoids drawn to the 50%probability level. The predicted structure was confirmed. The moleculesform an infinite hydrogen bonded chain via the NH3's along the a-axiswhich is the needle axis, as shown in FIG. 2. The absolute configurationwas determined to be Sat both C8 and C16 based upon the refinement ofthe flack parameter=0.02(5). The configuration of C16 was known to be S.

TABLE A1 Atomic coordinates (×10{circumflex over ( )}4) and equivalentisotropic displacement parameters (A{circumflex over ( )}2 ×10{circumflex over ( )}3). U(eq) is defined as one third of the trace ofthe orthogonalized Uij tensor. x y z U(eq) Br(1) 5816(1) 1172(1) 1875(1)34(1) S(1) −2800(2)   −1679(1)   1030(1) 28(1) O(1) 2992(7) −875(4)2278(1) 48(1) O(2) −1818(7)   −1946(3)   −193(1) 33(1) O(3) −1693(5)  1147(3)  −24(1) 27(1) O(4) −4576(7)   −176(3)  77(1) 32(1) N(1)  285(6)−1133(4)   1670(1) 22(1) N(2)  444(8)  26(3)  965(2) 25(1) N(3) 2679(10) 1576(4)  395(2) 23(1) C(1) 2242(9)  648(4) 1173(2) 20(1) C(2)3198(8)  351(4) 1606(2) 22(1) C(3)  2267(10) −571(4) 1891(2) 29(1) C(4)−474(9) −820(4) 1219(2) 20(1) C(5) −1135(9)   −2023(4)   1878(2) 25(1)C(6) −2805(11) −2394(5)   1565(2) 26(1) C(7)  −807(18) −2456(6)  2365(2) 41(2) C(8)  2920(10) 1736(4)  917(2) 23(1) C(9)  1254(13)2703(5) 1078(3) 32(2) C(10)  −755(11) −530(4) −802(2) 21(1) C(11)−2631(10) −858(4) −1102(2)   26(1) C(12) −2597(11) −528(5) −1570(2)  28(1) C(13)  −732(12)  127(4) −1755(2)   31(1) C(14)  1149(11)  434(5)−1457(2)   31(1) C(15)  1156(10)  102(4) −981(2) 26(1) C(16)  −926(12)−817(4) −274(2) 24(1) C(17) −2506(10)  130(4)  −50(2) 23(1)

TABLE A2 Bond lengths [Å] and angles (deg) Br(1)—C(2) 1.896(5) S(1)—C(4)1.714(5) S(1)—C(6) 1.719(6) O(1)—C(3) 1.215(6) O(2)—C(16) 1.413(6)O(3)—C(17) 1.260(6) O(4)—C(17) 1.256(6) N(1)—C(4) 1.387(6) N(1)—C(3)1.422(6) N(1)—C(5) 1.423(6) N(2)—C(4) 1.314(6) N(2)—C(1) 1.362(6)N(3)—C(8) 1.489(6) C(1)—C(2) 1.375(7) C(1)—C(8) 1.497(7) C(2)—C(3)1.431(7) C(5)—C(6) 1.350(8) C(5)—C(7) 1.474(8) C(8)—C(9) 1.521(8)C(10)—C(15) 1.385(8) C(10)—C(11) 1.395(7) C(10)—C(16) 1.529(7)C(11)—C(12) 1.375(7) C(12)—C(13) 1.385(8) C(13)—C(14) 1.388(8)C(14)—C(15) 1.394(8) C(16)—C(17) 1.538(7) C(4)—S(1)—C(6)  90.4(3)C(4)—N(1)—C(3) 121.2(4) C(4)—N(1)—C(5) 113.4(4) C(3)—N(1)—C(5) 125.4(4)C(4)—N(2)—C(1) 116.3(5) N(2)—C(1)—C(2) 122.2(5) N(2)—C(1)—C(8) 114.8(5)C(2)—C(1)—C(8) 122.7(5) C(1)—C(2)—C(3) 123.0(5) C(1)—C(2)—Br(1) 121.9(4)C(3)—C(2)—Br(1) 115.1(4) O(1)—C(3)—N(1) 121.2(5) O(1)—C(3)—C(2) 126.8(5)N(1)—C(3)—C(2) 111.9(5) N(2)—C(4)—N(1) 125.1(5) N(2)—C(4)—S(1) 123.6(4)N(1)—C(4)—S(1) 111.3(3) C(6)—C(5)—N(1) 110.0(5) C(6)—C(5)—C(7) 125.9(5)N(1)—C(5)—C(7) 124.1(5) C(5)—C(6)—S(1) 114.8(5) N(3)—C(8)—C(1) 110.5(4)N(3)—C(8)—C(9) 109.4(5) C(1)—C(8)—C(9) 108.6(4) C(15)—C(10)—C(11)119.6(5) C(15)—C(10)—C(16) 121.2(5) C(11)—C(10)—C(16) 119.1(5)C(12)—C(11)—C(10) 119.8(5) C(11)—C(12)—C(13) 121.5(6) C(12)—C(13)—C(14)118.4(5) C(13)—C(14)—C(15) 121.0(5) C(10)—C(15)—C(14) 119.6(5)O(2)—C(16)—C(10) 112.3(4) O(2)—C(16)—C(17) 113.0(5) C(10)—C(16)—C(17)106.3(4) O(4)—C(17)—O(3) 125.1(5) O(4)—C(17)—C(16) 116.1(5)O(3)—C(17)—C(16) 118.8(5)

TABLE A3 Anisotropic displacement parameters (A{circumflex over ( )}2 ×10{circumflex over ( )}3) (symmetry transformations used to generateequivalent atoms. The anisotropic displacement factor exponent takes theform: −2 pi{circumflex over ( )}2 [h{circumflex over ( )}2 a*{circumflexover ( )}2 U11 + . . . + 2 h k a* b* U12) U11 U22 U33 U23 U13 U12 Br(1)27(1) 40(1) 36(1) −4(1) −6(1) −9(1) S(1) 27(1) 24(1) 33(1)  2(1) −5(1)−7(1) O(1) 54(3) 56(3) 33(3)  9(2) −21(2)  −11(2)  O(2) 41(3) 13(2)46(3)  3(2)  6(2)  4(2) O(3) 33(2) 14(2) 35(2)  5(2) −7(1)  0(2) O(4)31(3) 21(2) 44(3) −1(2)  8(2)  0(2) N(1) 22(2) 22(2) 21(2)  1(2) −3(2)−3(2) N(2) 26(3) 21(2) 26(3)  5(2) −2(2)  0(2) N(3) 27(3) 22(3) 19(3) 4(2)  3(2) −8(2) C(1) 16(3) 19(3) 26(3) −4(2)  0(2) −3(2) C(2) 13(3)23(3) 29(3)  1(3)  1(2) −2(2) C(3) 29(3) 31(3) 27(3) −1(3) −5(3)  2(3)C(4) 23(3) 17(3) 20(3)  4(2)  0(2)  1(2) C(5) 26(3) 22(3) 29(3) 11(3) 6(3) −2(2) C(6) 22(3) 17(3) 40(4)  4(3)  0(3) −4(3) C(7) 56(5) 36(4)31(4) 11(3)  1(4) −2(4) C(8) 23(3) 21(3) 26(3) −7(3) −4(2) −4(2) C(9)34(5) 21(3) 41(5) −3(3)  6(3) −9(3) C(10) 23(3) 17(3) 23(3)  1(2)  6(3) 9(3) C(11) 26(3) 22(3) 31(4)  1(3)  3(3) −6(3) C(12) 26(3) 19(3) 38(4)−7(3) −4(3) 11(3) C(13) 37(3) 22(3) 32(4)  3(2)  5(3)  8(3) C(14) 22(4)25(3) 45(4)  8(3) 10(3)  0(3) C(15) 27(3) 20(3) 33(3) −1(3)  7(3)  6(3)C(16) 30(3) 10(3) 31(3) −2(2)  1(3)  3(3) C(17) 29(3) 18(3) 22(3)  1(2)−3(3)  6(3)

TABLE A4 Hydrogen coordinates (×10{circumflex over ( )}4) and isotropicdisplacement parameters (A{circumflex over ( )}2 × 10{circumflex over( )}3) x y z U(eq) H(2) −3600(200)   −1860(80)   −110(30) 160(40)  H(3)4250(110)  910(50)  254(19) 59(17) H(3A) 1260(150) 1240(60)  310(20)80(20) H(3B) 2910(100) 2160(50)  266(19) 27(18) H(6) −3610(100)  −2890(40)   1579(18) 25(18) H(7) −2240(160)   −3020(80)   2480(30)120(30)  H(7A) −1360(90)    −1900(50)   2583(17) 30(17) H(7B)  640(120)−2750(50)   2426(19) 41(19) H(8) 4800(80)  1970(40) 1003(17) 28(15) H(9)2070(100) 3440(50)  950(20) 56(19) H(9A) 1570(110) 2790(50) 1430(20)60(20) H(9B) −210(100) 2520(50) 1035(19) 34(19) H(11) −3890(80)   −1350(40)   −963(14) 16(12) H(12) −3720(100)   −740(50) −1780(20)  60(20) H(13) −670(100)  380(40) −2129(18)   40(15) H(14) 2390(110) 910(50) −1573(18)   45(17) H(15) 2710(120)  320(50) −760(20) 70(20)H(16)  780(100)  840(40) −125(18) 50(16)

TABLE A5 Torsion angles [deg]. C(4)—N(2)—C(1)—C(2) 5.5(7)C(4)—N(2)—C(1)—C(8) −168.8(4) N(2)—C(1)—C(2)—C(3) −5.2(8)C(8)—C(1)—C(2)—C(3) 168.7(5) N(2)—C(1)—C(2)—Br(1) 176.5(4)C(8)—C(1)—C(2)—Br(1) −9.6(7) C(4)—N(1)—C(3)—O(1) −177.1(5)C(5)—N(1)—C(3)—O(1) 4.4(8) C(4)—N(1)—C(3)—C(2) 3.3(7)C(5)—N(1)—C(3)—C(2) −175.2(4) C(1)—C(2)—C(3)—O(1) −179.0(5)Br(1)—C(2)—C(3)—O(1) −0.7(8) C(1)—C(2)—C(3)—N(1) 0.6(7)Br(1)—C(2)—C(3)—N(1) 179.0(3) C(1)—N(2)—C(4)—N(1) −1.5(7)C(1)—N(2)—C(4)—S(1) 178.2(4) C(3)—N(1)—C(4)—N(2) −3.0(7)C(5)—N(1)—C(4)—N(2) 175.6(5) C(3)—N(1)—C(4)—S(1) 177.2(4)C(5)—N(1)—C(4)—S(1) −4.1(5) C(6)—S(1)—C(4)—N(2) −177.2(5)C(6)—S(1)—C(4)—N(1) 2.5(4) C(4)—N(1)—C(5)—C(6) 3.8(6)C(3)—N(1)—C(5)—C(6) −177.6(5) C(4)—N(1)—C(5)—C(7) −175.8(6)C(3)—N(1)—C(5)—C(7) 2.8(8) N(1)—C(5)—C(6)—S(1) −1.8(6)C(7)—C(5)—C(6)—S(1) 177.7(5) C(4)—S(1)—C(6)—C(5) −0.4(5)N(2)—C(1)—C(8)—N(3) −34.3(6) C(2)—C(1)—C(8)—N(3) 151.4(5)N(2)—C(1)—C(8)—C(9) 85.7(6) C(2)—C(1)—C(8)—C(9) −88.6(6)C(15)—C(10)—C(11)—C(12) −1.5(8) C(16)—C(10)—C(11)—C(12) 174.9(5)C(10)—C(11)—C(12)—C(13) 0.0(8) C(11)—C(12)—C(13)—C(14) 1.0(8)C(12)—C(13)—C(14)—C(15) −0.6(8) C(11)—C(10)—C(15)—C(14) 1.9(8)C(16)—C(10)—C(15)—C(14) −174.4(5) C(13)—C(14)—C(15)—C(10) −0.9(8)C(15)—C(10)—C(16)—O(2) −141.3(5) C(11)—C(10)—C(16)—O(2) 42.3(7)C(15)—C(10)—C(16)—C(17) 94.7(6) C(11)—C(10)—C(16)—C(17) −81.7(6)O(2)—C(16)—C(17)—O(4) −15.1(7) C(10)—C(16)—C(17)—O(4) 108.4(5)O(2)—C(16)—C(17)—O(3) 167.6(4) C(10)—C(16)—C(17)—O(3) −68.9(6)

Example 176-(3,5-difluorophenyl)-3-methyl-7-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onehydrochloride (0.030 g, 0.084 mmol), 4-chloropyrrolo[2,3-d]pyrimidine(0.013 g, 0.084 mmol), and N, N-diisopropylethylamine (0.044 mL, 0.25mmol) in isopropyl alcohol (0.2 mL) was heated at 100° C., in a sealedtube, for three days. The resultant mixture was applied on RP-HPLC(XBridge C18 Column, eluting with a gradient of acetonitrile/watercontaining 0.15% NH₄OH) to give the desired product. LCMS calculated forC₂₁H₁₇F₂N₆OS (M+H)⁺: m/z=439.1. Found: 439.1.

Example 186-(3,5-difluorophenyl)-7-{1-[(2-fluoro-9H-purin-6-yl)amino]ethyl}-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onehydrochloride (0.030 g, 0.084 mmol), 2-fluoro-6-chloropurine (0.015 g,0.084 mmol), and N,N-diisopropylethylamine (0.044 mL, 0.25 mmol) inisopropyl alcohol (0.2 mL) was heated at 100° C. for three days, in asealed tube. The resultant mixture was purified on RP-HPLC (XBridge C18Column, eluting with a gradient of acetonitrile/water containing 0.15%NH₄OH) to give the desired product. LCMS calculated for C₂₀H₁₅F₃N₇OS(M+H)⁺: m/z=458.1. Found: 458.0.

Example 193-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-pyridin-4-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1.7-(1-aminoethyl)-3-methyl-6-pyridin-4-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-3-methyl-6-pyridin-4-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.050 g, 0.16 mmol) in tetrahydrofuran (0.5 mL) and water (0.12 mL) wasadded 1.00 M of trimethylphosphine in tetrahydrofuran (0.19 mL, 0.19mmol) at room temperature and the mixture was stirred at roomtemperature for 1 hour. To the mixture was added ethyl acetate (EtOAc)and the mixture was extracted with 1 N HCl two times. The combinedextracts were neutralized with solid sodium bicarbonate, and extractedwith dichloromethane. The combined organic layers were washed withbrine, dried over magnesium sulfate, and concentrated under reducedpressure. The residue, shown two peaks with same desired mass, was useddirectly in next step. LCMS calculated for C₁₄H₁₅N₄OS (M+H)⁺: m/z=287.1.Found: 287.0.

Step 2.3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-pyridin-4-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 6-bromo-9H-purine (0.064 g, 0.32 mmol),7-(1-aminoethyl)-3-methyl-6-pyridin-4-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.046 g, 0.16 mmol), and N,N-diisopropylethylamine (0.056 mL, 0.32mmol) in ethanol (0.5 mL) was heated at reflux under nitrogen overnight.The mixture was evaporated and the resultant residue was purified onRP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile/water containing 0.15% NH₄OH) to give the product as thefree base. LCMS calculated for C₁₉H₁₇N₈OS (M+H)⁺: m/z=405.1. Found:405.1.

Example 203-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-(1,3-thiazol-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-3-methyl-6-(1,3-thiazol-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.10 g, 0.32 mmol), and 2-(tributylstannyl)-1,3-thiazole (143 mg, 0.382mmol) in 1,4-dioxane (3 mL) was addedtetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol). Thereaction mixture was heated at 120° C. overnight. After cooling to roomtemperature, the mixture concentrated under reduced pressure. The crudemixture was purified on silica gel, eluting with 0 to 60% ethyl acetatein hexane, to give the desired product (73 mg, 72%). LCMS calculated forC₁₂H₁₁N₆OS₂(M+H)⁺: m/z=319.0. Found: 319.0.

Step 2.7-(1-aminoethyl)-3-methyl-6-(1,3-thiazol-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-3-methyl-6-(1,3-thiazol-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.030 g, 0.094 mmol) in tetrahydrofuran (0.3 mL) and water (0.068 mL)was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.11 mL, 0.11mmol) at room temperature and the mixture was stirred at roomtemperature for 1 hour. To the mixture was added ethyl acetate and themixture was extracted with 1 N HCl two times. The combined extracts wereneutralized with solid sodium bicarbonate, and extracted withdichloromethane. The combined organic layers were washed with brine,dried over magnesium sulfate, and concentrated under reduced pressure.The residue was used directly in next step. LCMS calculated forC₁₂H₁₃N₄OS₂(M+H)⁺: m/z=293.1. Found: 293.0.

Step 3.3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-(1,3-thiazol-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of 6-bromo-9H-purine (0.038 g, 0.19 mmol),7-(1-aminoethyl)-3-methyl-6-(1,3-thiazol-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.028 g, 0.096 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.19mmol) in ethanol (0.3 mL) was heated at reflux under nitrogen overnight.The mixture was evaporated and the resultant residue was purified onRP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile/water containing 0.05% trifluoroacetic acid (TFA)) to givethe product as a TFA salt. LCMS calculated for C₁₇H₁₅N₈OS₂(M+H)⁺:m/z=411.1. Found: 411.0.

Example 213-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-(1,3-thiazol-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-3-methyl-6-(1,3-thiazol-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.10 g, 0.32 mmol) and 4-(tributylstannyl)-1,3-thiazole (143 mg, 0.382mmol) in 1,4-dioxane (3 mL) was addedtetrakis(triphenylphosphine)palladium(0) (18.4 mg, 0.0159 mmol). Thereaction mixture was heated at 120° C. overnight. After cooling to roomtemperature, the mixture concentrated under reduced pressure. The crudemixture was purified on silica gel, eluting with 0 to 60% EtOAc inhexane, to give the desired product (82 mg, 81%). LCMS calculated forC₁₂H₁₁N₆OS₂(M+H)⁺: m/z=319.0. Found: 319.0.

Step 2.7-(1-aminoethyl)-3-methyl-6-(1,3-thiazol-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-3-methyl-6-(1,3-thiazol-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.030 g, 0.094 mmol) in tetrahydrofuran (0.3 mL) and water (0.068 mL)was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.113 mL,0.113 mmol) at room temperature and the mixture was stirred at roomtemperature for 1 hour. To the mixture was added ethyl acetate and themixture was extracted with 1 N HCl two times. The combined extracts wereneutralized with solid sodium bicarbonate, and extracted withdichloromethane. The combined organic layers were washed with brine,dried over magnesium sulfate, and concentrated under reduced pressure.The residue was used directly in next step. LCMS calculated forC₁₂H₁₃N₄OS₂(M+H)⁺: m/z=293.1. Found: 293.0.

Step 3.3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-(1,3-thiazol-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of 6-bromo-9H-purine (0.038 g, 0.19 mmol),7-(1-aminoethyl)-3-methyl-6-(1,3-thiazol-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.028 g, 0.096 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.19mmol) in ethanol (0.3 mL) was heated at reflux under nitrogen overnight.The mixture was evaporated and the resultant residue was purified onRP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA) to give the product as a TFAsalt. LCMS calculated for C₁₇H₁₅N₈OS₂(M+H)⁺: m/z=411.1. Found: 411.0.

Example 226-(4-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-6-(4-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.10 g, 0.32 mmol) and 4-fluorophenylboronic acid (53 mg, 0.38 mmol) in1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate in water(0.38 mL, 0.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (18mg, 0.016 mmol). The reaction mixture was heated at 100° C. overnight.After cooling to room temperature, the mixture was diluted with ethylacetate, washed with water, brine, dried over MgSO₄, and concentrated.The crude mixture was purified on silica gel, eluting with 0 to 40%EtOAc in hexane, to give the desired product (69 mg, 66%). LCMScalculated for C₁₅H₁₃FN₅OS (M+H)⁺: m/z=330.1. Found: 330.0.

Step 2.7-(1-aminoethyl)-6-(4-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-(4-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.062 g, 0.19 mmol) in tetrahydrofuran (0.6 mL) and water (0.14 mL,)was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.226 mL,0.226 mmol) at room temperature, and the mixture was stirred at roomtemperature for 1 hour. To the mixture was added ethyl acetate, and thenthe mixture was extracted with 1 N HCl two times. The combined extractswere neutralized with solid sodium bicarbonate and extracted withdichloromethane. The combined organic layers were washed with brine,dried over magnesium sulfate, and concentrated under reduced pressure.The residue was used directly in next step. LCMS calculated forC₁₅H₁₅FN₃OS (M+H)⁺: m/z=304.1. Found: 304.1.

Step 3.6-(4-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of 6-bromo-9H-purine (0.076 g, 0.38 mmol),7-(1-aminoethyl)-6-(4-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.058 g, 0.19 mmol), and N,N-diisopropylethylamine (0.066 mL, 0.38mmol) in ethanol (0.6 mL) was heated at reflux under nitrogen overnight.The mixture was evaporated, and the resultant residue was purified onRP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA) to give the product as a TFAsalt. LCMS calculated for C₂₀H₁₇FN₇OS (M+H)⁺: m/z=422.1. Found: 422.1.

Example 237-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1.7-(1-azidoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(1.24 g, 3.95 mmol) and (3,5-difluorophenyl)boronic acid (0.748 g, 4.74mmol) in 1,4-dioxane (25 mL) was added a 1 N solution of sodiumcarbonate in water (5.92 mL, 5.92 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.24 mmol). Themixture was heated at 100° C. overnight. After cooling, the mixture wasdiluted with ethyl acetate, washed with water and brine, dried overMgSO₄, and concentrated. The residue was purified on silica gel (0-40%EtOAc/Hex) to give the desired product (0.42 g, 31%). LCMS calculatedfor C₁₅H₁₂F₂N₅OS (M+H)⁺: m/z=348.1. Found: 348.0. The product wassubjected to chiral HPLC separation (ChiralPak IA Column: 20×250 mm, 5μm; Mobile Phase: 5% Ethanol 95% Hexanes; Flow Rate: 15 mL/min) to givetwo enantiomers. On analytic HPLC (ChiralPak IA Column: 4.6×250 mm, 5μm; Mobile Phase: 5% Ethanol-95% Hexanes; Flow Rate: 1 mL/min), thefirst enantiomer has retention time of 7.78 min and the second peak hasretention time of 8.61 minutes.

Step 2.7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solutions of7-(1-azidoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.15 g, 0.43 mmol) (1 st peak from chiral separation) intetrahydrofuran (2 mL) and water (0.5 mL) were added 1.00 M oftrimethylphosphine in tetrahydrofuran (0.52 mL, 0.52 mmol) at roomtemperature and the mixtures were stirred at room temperature for 1hour. To the mixture was added EtOAc and the mixture was extracted withaqueous 1 N HCl solution (three times). The combined extracts wereneutralized with solid Na₂CO₃ and extracted with dichloromethane (twotimes). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated to give the desired product (134 mg, 96.6%).LCMS calculated for C₁₅H₁₄F₂N₃OS (M+H)⁺: m/z=322.1. Found: 322.0.

Step 3.7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of optical pure7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.13 g, 0.40 mmol) made from above, 2-amino-6-bromopurine (0.10 g, 0.47mmol), and N,N-diisopropylethylamine (0.085 mL, 0.49 mmol) in ethanol (1mL) was heated at 110° C. overnight. LCMS showed incomplete conversion.An additional 0.5 equivalent of 2-amino-6-bromopurine and 1.0 equivalentof N,N-diisopropylethylamine was added, and the mixture was stirred at110° C. for another day. The solid was shown to be 2-amino-6-bromopurineby LCMS. The mixture was filtered, and the filtrates were purified onpreparative-LCMS ((XBridge C18 Column, eluting with a gradient ofacetonitrile/water containing 0.15% NH₄OH) to give the desired product(0.095 g, 52%). LCMS calculated for C₂₀H₁₇F₂N₈OS (M+H)⁺: m/z=455.1.Found: 455.1 ¹H NMR (DMSO-d₆, 400 MHz) δ 7.67 (1H, s), 7.27 (1H, m),7.17 (3H, m), 7.07 (1H, s), 6.89 (1H, br s), 5.45 (2H, br s), 5.03 (1H,m), 2.63 (3H, s), 1.30 (3H, d, J=6.8 Hz) ppm. ¹⁹F NMR (DMSO-d₆, 376.3MHz) δ −111 ppm.

Example 247-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1. 7-(1-bromoethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of polyphosphoric acid (73.8 g, 677 mmol), 1,3-thiazol-2-amine(12.3 g, 123 mmol), and methyl 4-bromo-3-oxopentanoate (34.8 g, 166mmol) was stirred at 110° C. overnight. After cooling, an ice-cold 10%aq. NaOH solution was slowly added to adjust the pH to 7. The mixturewas filtered, and the collected precipitate was air-dried to give crudeproduct which was directly used in next step. LCMS calculated forC₈H₈BrN₂OS (M+H)⁺: m/z=259.0. Found: 259.0.

Step 2. 6-bromo-7-(1-bromoethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 7-(1-bromo ethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(17.5 g, 67.5 mmol) and N-bromosuccinimide (14.2 g, 79.8 mmol) inacetonitrile (400 mL) was stirred at 80° C. under N₂ overnight. Afterremoval of the solvent under reduced pressure, the resulting solid wasdissolved in dichloromethane, washed sequentially with water, saturatedaqueous Na₂S₂O₃ and NaHCO₃ solution and brine, dried over Na₂SO₄, andthen concentrated to give crude product (3.7 g), which was used in thenext step without further purification. LCMS calculated for C₈H₇Br₂N₂OS(M+H)⁺: m/z=336.9. Found: 336.9.

Step 3. 7-(1-azidoethyl)-6-bromo-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of6-bromo-7-(1-bromoethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (3.7 g,11 mmol) and sodium azide (1.4 g, 22 mmol) in N,N-dimethylformamide (30mL) was stirred at room temperature for 1.5 hour. After diluted withethyl acetate, the mixture was washed with water, dried over Na₂SO₄,concentrated and purified on silica gel (0-60% ethyl acetate/hexanes) togive the desired product (2.16 g). LCMS calculated for C₈H₇BrN₅OS(M+H)⁺: m/z=300.0. Found: 300.0.

Step 4.7-(1-azidoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.50 g,1.7 mmol) and (3,5-difluorophenyl)boronic acid (0.31 g, 2.0 mmol) in1,4-dioxane (10 mL) was added a 1 N solution of sodium carbonate inwater (2.2 mL, 2.2 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.096 g, 0.083 mmol). The mixture was stirred at 100° C. overnight.After cooling, the mixture was diluted with ethyl acetate, washed withwater and brine, dried over MgSO₄, concentrated, and purified on silicagel (0-45% ethyl acetate/hexanes) to give the desired product (0.30 g,53%). LCMS calculated for C₁₄H₁₀F₂N₅OS (M+H)⁺: m/z=334.1. Found: 334.0.

Step 5.7-(1-aminoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.295 g, 0.885 mmol) in tetrahydrofuran (5 mL) and water (1 mL) wasadded 1.00 M of trimethylphosphine in tetrahydrofuran (1.06 mL, 1.06mmol) at room temperature and the mixture was stirred at roomtemperature for 1 hour. To the mixture was added ethyl acetate, and themixture was extracted with aqueous 1 N HCl solution (three times). Thecombined extract was neutralized with solid NaHCO₃ and extracted withdichloromethane (two times). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to give the desiredcompound (0.241 g, 88.6%), which was used directly in next step. LCMScalculated for C₁₄H₁₂F₂N₃OS (M+H)⁺: m/z=308.1. Found: 308.0.

Step 6.7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of7-(1-aminoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.040 g, 0.13 mmol), 2-amino-6-bromopurine (0.056 g, 0.26 mmol), andN,N-diisopropylethylamine (0.045 mL, 0.26 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.15% NH₄OH), to give thedesired product. LCMS calculated for C₁₉H₁₅F₂N₈OS (M+H)⁺: m/z=441.1.Found: 441.1.

Example 256-(3,5-difluorophenyl)-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of7-(1-aminoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.037 g, 0.12 mmol), 6-bromo-9H-purine (0.048 g, 0.24 mmol), andN,N-diisopropylethylamine (0.042 mL, 0.24 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.15% NH₄OH) to give thedesired product. LCMS calculated for C₁₉H₁₄F₂N₇OS (M+H)⁺: m/z=426.1.Found: 426.0. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.99 (1H, d, J=4.8 Hz), 7.63(1H, s), 7.53 (1H, d, J=4.8 Hz), 7.24 (1H, m), 7.16 (2H, m), 6.88 (1H,br s), 5.41 (2H, br s), 5.05 (1H, m), 1.27 (3H, d, J=6.8 Hz) ppm. ¹⁹FNMR (DMSO-d₆, 376.3 MHz) δ −111 ppm.

Example 267-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1.7-(1-azidoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.48 g,1.6 mmol) and (3-fluorophenyl)boronic acid (0.27 g, 2.0 mmol) in1,4-dioxane (10 mL) was added a 1 N solution of sodium carbonate inwater (2.1 mL, 2.1 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.092 g, 0.080 mmol). The mixture was stirred at 100° C. overnight.After cooling, the mixture was diluted with ethyl acetate, washed withwater and brine, dried over MgSO₄, concentrated, and purified on silicagel (0-50% ethyl acetate/hexanes) to give the desired compound (0.32 g,63%). LCMS calculated for C₁₄H₁₁FN₅OS (M+H)⁺: m/z=316.1. Found: 316.0.

Step 2.7-(1-aminoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.32 g, 1.0 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added1.00 M of trimethylphosphine in tetrahydrofuran (1.22 mL, 1.22 mmol) atroom temperature, and the mixture was stirred at room temperature for 1hour. To the mixture was added ethyl acetate, and the mixture wasextracted with aqueous 1 N HCl solution (three times). The combinedextract was neutralized with solid NaHCO₃ and extracted withdichloromethane (two times). The combined organic layer was washed withbrine, dried over Na₂SO₄, and concentrated to give the desired product(0.17 g, 58%). LCMS calculated for C₁₄H₁₃FN₃OS (M+H)⁺: m/z=290.1. Found:290.0.

Step 3.7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of 7-(1-aminoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025g, 0.086 mmol), 2-amino-6-bromopurine (0.033 g, 0.16 mmol), andN,N-diisopropylethylamine (0.027 mL, 0.16 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.15% NH₄OH) to give thedesired product. LCMS calculated for C₁₉H₁₆FN₈OS (M+H)⁺: m/z=423.1.Found: 423.0. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.98 (1H, d, J=4.8 Hz), 7.63(1H, s), 7.52 (1H, d, J=4.8 Hz), 7.46 (1H, m), 7.20 (2H, m), 6.84 (1H,br s), 5.41 (1H, br s), 5.07 (1H, m), 1.26 (3H, d, J=6.8 Hz) ppm. ¹⁹FNMR (DMSO-d₆, 376.3 MHz) δ −114 ppm.

Example 277-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1. 7-(1-azidoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.34 g,1.1 mmol) and phenylboronic acid (0.16 g, 1.4 mmol) in 1,4-dioxane (10mL) was added a 1 N solution of sodium carbonate in water (1.5 mL, 1.5mmol) and tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.057mmol). The mixture was stirred at 100° C. overnight. After cooling, themixture was diluted with ethyl acetate, washed with water and brine,dried over MgSO₄, concentrated, and purified on silica gel (0-50% ethylacetate/hexanes) to give the desired product (0.23 g, 68%). LCMScalculated for C₁₄H₁₂N₅OS (M+H)⁺: m/z=298.1. Found: 298.0.

Step 2. 7-(1-aminoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.23g, 0.77 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added 1.00M of trimethylphosphine in tetrahydrofuran (0.93 mL, 0.93 mmol) at roomtemperature, and the mixture was stirred at room temperature for 1 hour.To the mixture was added ethyl acetate, and the mixture was extractedwith aqueous 1 N HCl solution (three times). The combined extract wasneutralized with solid NaHCO₃ and extracted with dicloromethane (twotimes). The combined organic layer was washed with brine, dried overNa₂SO₄, and concentrated to give the desired compound (0.13 g, 62%).LCMS calculated for C₁₄H₁₄N₃OS (M+H)⁺: m/z=272.1. Found: 272.0.

Step 3.7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of7-(1-aminoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025g, 0.092 mmol), 2-amino-6-bromopurine (0.035 g, 0.16 mmol), andN,N-diisopropylethylamine (0.029 mL, 0.16 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.15% NH₄OH) to give thedesired product. LCMS calculated for C₁₉H₁₇N₈OS (M+H)⁺: m/z=405.1.Found: 405.1. ¹H NMR (DMSO-d₆, 400 MHz) δ 80.1 (1H, d, J=4.8 Hz), 7.65(1H, s), 7.55 (1H, d, J=4.8 Hz), 7.47 (2H, m), 7.40 (3H, m), 6.79 (1H,br s), 5.48 (2H, br s), 5.13 (1H, m), 1.29 (3H, d, J=6.8 Hz) ppm.

Example 286-(3-fluorophenyl)-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of7-(1-aminoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.025 g, 0.086 mmol), 6-bromo-9H-purine (0.031 g, 0.16 mmol), andN,N-diisopropylethylamine (0.027 mL, 0.16 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.15% NH₄OH) to give thedesired product. LCMS calculated for C₁₉H₁₅FN₇OS (M+H)⁺: m/z=408.1.Found: 408.0.

Example 296-phenyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of7-(1-aminoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025g, 0.092 mmol), 6-bromo-9H-purine (0.033 g, 0.16 mmol), andN,N-diisopropylethylamine (0.029 mL, 0.16 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.15% NH₄OH) to give thedesired product. LCMS calculated for C₁₉H₁₆N₇OS (M+H)⁺: m/z=390.1.Found: 390.1. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.08 (1H, s), 8.06 (1H, s),7.97 (1H, d, J=4.8 Hz), 7.51 (1H, d, J=4.8 Hz), 7.44˜7.33 (6H, m), 5.15(1H, m), 1.29 (3H, d, J=7.2 Hz) ppm.

Example 306-(3-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1.7-(1-azidoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.50 g,1.6 mmol) and (3-fluorophenyl)boronic acid (0.27 g, 1.9 mmol) in1,4-dioxane (10 mL) was added 1 N solution of sodium carbonate in water(2.1 mL, 2.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.092g, 0.080 mmol). The mixture was stirred at 100° C. overnight. Aftercooling, the mixture was diluted with ethyl acetate, washed with water,dried over Na₂SO₄, concentrated and purified on silica gel (0-40% ethylacetate/hexanes) to give the desired product (0.32 g, 61%). LCMScalculated for C₁₅H₁₃FN₅OS (M+H)⁺: m/z=330.1. Found: 330.0. The productwas subjected to chiral HPLC separation (ChiralPak IA Column: 20×250 mm,5 μm; Mobile Phase: 10% Ethanol 90% Hexanes; Flow Rate: 18 mL/min) togive two enantiomers. On analytic HPLC (ChiralPak IA Column: 4.6×250 mm,5 μm; Mobile Phase: 10% Ethanol-90% Hexanex; Flow Rate: 1 mL/min), thefirst enantiomer has retention time of 6.38 minutes and the second peakhas retention time of 6.99 minutes.

Step 2.7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.14 g, 0.42 mmol) (1^(st) peak from chiral separation) intetrahydrofuran (3 mL) and water (0.5 mL) was added 1.00 M oftrimethylphosphine in tetrahydrofuran (0.52 mL, 0.52 mmol), and themixture was stirred at room temperature for 1 hour. To the mixtures wereadded ethyl acetate and the mixtures were extracted with aqueous 1 N HClsolution (three times). The combined extracts were neutralized withsolid NaHCO₃, and extracted with dichloromethane (three times). Thecombined organic layers were washed with brine, dried over MgSO₄, andconcentrated to give the crude product (0.125 g) used directly in nextstep. LCMS calculated for C₁₅H₁₅FN₃OS (M+H)⁺: m/z=304.1. Found: 304.0.

Step 3.6-(3-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of single enantiomer7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.125 g, 0.412 mmol) made from above, 6-bromo-9H-purine (0.148 g, 0.742mmol), and N,N-diisopropylethylamine (0.144 mL, 0.824 mmol) in ethanol(1.5 mL) was heated at 110° C. overnight. The mixture was filtered, andthe filtrate was purified on preparative-LCMS (XBridge C18 Column,eluting with a gradient of acetonitrile/water containing 0.15% NH₄OH) togive the desired product (0.076 g, 44%). LCMS calculated for C₂₀H₁₇FN₇OS(M+H)⁺: m/z=422.1. Found: 422.0. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.05 (2H,s), 7.43 (1H, m), 7.24˜7.14 (5H, m), 6.99 (1H, s), 5.08 (1H, m), 2.59(3H, s), 1.29 (3H, d, J=6.5 Hz) ppm. ¹⁹F NMR (DMSO-d₆, 376.3 MHz) δ −114ppm.

Example 313-methyl-6-(4-methylphenyl)-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-3-methyl-6-(4-methylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.080 g, 0.25 mmol) and (4-methylphenyl)boronic acid (0.042 g, 0.31mmol) in 1,4-dioxane (2 mL) was added 1 N solution of sodium carbonatein water (0.38 mL, 0.38 mmol) anddichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(0.011 g, 0.015 mmol). The mixture was heated at 100° C. overnight.After cooling to room temperature, the mixture was diluted with ethylacetate, washed with water, dried over MgSO₄, concentrated and thenpurified on silica gel (0-25% ethyl acetate/hexane) to give the desiredproduct (50 mg). LCMS calculated for C₁₆H₁₆N₅OS (M+H)⁺: m/z=326.1.Found: 326.0.

Step 2.7-(1-aminoethyl)-3-methyl-6-(4-methylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-(1-azidoethyl)-3-methyl-6-(4-methylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.050 g, 0.15 mmol) in tetrahydrofuran (2 mL) was added 1.00 M oftrimethylphosphine in tetrahydrofuran (0.23 mL, 0.23 mmol) and themixture was stirred at room temperature for 1 hour. The mixture wasconcentrated to give the crude product (40 mg), which was used directlyin next step. LCMS calculated for C₁₆H₁₈N₃OS (M+H)⁺: m/z=300.1. Found:300.1.

Step 3.3-methyl-6-(4-methylphenyl)-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-c]pyrimidin-5-one

A mixture of7-(1-aminoethyl)-3-methyl-6-(4-methylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.040 g, 0.13 mmol), 6-bromo-9H-purine (0.040 g, 0.20 mmol), andN,N-diisopropylethylamine (0.046 mL, 0.27 mmol) in ethanol (0.3 mL) washeated at 110° C. overnight. The mixture was filtered and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA), to give thedesired product as a TFA salt. LCMS calculated for C₂₁H₂₀N₇OS (M+H)⁺:m/z=418.1. Found: 418.1. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.57 (1H, br s),8.39 (1H, s), 8.38 (1H, s), 7.19 (4H, s), 7.02 (1H, d, J=1.2 Hz), 5.17(1H, m), 2.59 (3H, s), 2.30 (3H, s), 1.32 (3H, d, J=6.8 Hz) ppm.

Example 327-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-6-(3-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.12 g, 0.38 mmol) and (3-chlorophenyl)boronic acid (0.072 g, 0.46mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodium carbonatein water (0.5 mL, 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.022 g, 0.019 mmol). The mixture was stirred at 100° C. overnight.After cooling, the mixture was diluted with ethyl acetate, washed withwater, dried over Na₂SO₄, concentrated, and purified on silica gel(0-30% ethyl acetate/hexanes) to give the desired product. LCMScalculated for C₁₅H₁₃ClN₅OS (M+H)⁺: m/z=346.1. Found: 346.0.

Step 2.7-(1-aminoethyl)-6-(3-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-(3-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.10 g, 0.29 mmol) in tetrahydrofuran (3 mL, 40 mmol) was added 1.00 Mof trimethylphosphine in tetrahydrofuran (0.35 mL, 0.35 mmol), and themixture was stirred at room temperature for 1 hour. The mixture wasconcentrated to give the crude product (0.090 g), which was useddirectly in next step. LCMS calculated for C₁₅H₁₅ClN₃OS (M+H)⁺:m/z=320.1. Found: 320.0.

Step 3.7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of7-(1-aminoethyl)-6-(3-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.045 g, 0.14 mmol), 2-amino-6-bromopurine (0.060 g, 0.28 mmol), andN,N-diisopropylethylamine (0.049 mL, 0.28 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA) to give the desiredproduct as a TFA salt. LCMS calculated for C₂₀H₁₈ClN₈OS (M+H)⁺:m/z=453.1. Found: 453.1. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.13 (1H, s),7.48˜7.12 (8H, s), 6.55 (1H, br s), 5.14 (1H, m), 1.33 (3H, d, J=6.8 Hz)ppm.

Example 337-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(2-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-6-(2-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.12 g, 0.38 mmol) and (2-fluorophenyl)boronic acid (0.064 g, 0.46mmol) in 1,4-dioxane (4 mL) was added a 1 N solution of sodium carbonatein water (0.8 mL, 0.8 mmol) anddichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(0.014 g, 0.019 mmol). The mixture was stirred at 100° C. overnight.After cooling, the mixture was diluted with ethyl acetate, washed withwater, dried over Na₂SO₄, concentrated, and purified on silica gel(0-35% ethyl acetate/hexane) to give the desired product (87 mg). LCMScalculated for C₁₅H₁₃FN₅OS (M+H)⁺: m/z=330.1. Found: 330.0.

Step 2.7-(1-aminoethyl)-6-(2-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-(2-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.087 g, 0.26 mmol) in tetrahydrofuran (3 mL) was added 1.00 M oftrimethylphosphine in tetrahydrofuran (0.32 mL, 0.32 mmol), and themixture was stirred at room temperature for 1 hour. The mixture wasconcentrated to give the crude product (0.080 g), which was useddirectly in next step. LCMS calculated for C₁₅H₁₅FN₃OS (M+H)⁺:m/z=304.1. Found: 304.0.

Step 3.7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(2-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of 7-(1-aminoethyl)-6-(2-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.040 g, 0.13 mmol), 2-amino-6-bromopurine (0.056 g, 0.26 mmol), andN,N-diisopropylethylamine (0.046 mL, 0.26 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA) to give the desiredproduct as a diastereoisomeric mixture (TFA salts). LCMS calculated forC₂₀H₁₈FN₈OS (M+H)⁺: m/z=437.1. Found: 437.1. ¹H NMR (DMSO-d₆, 400 MHz) δ8.77 (1H, br s), 8.14 (1H, m), 7.45 (2H, m), 7.28 (4H, m), 7.14 (1H, m),5.13 (1H, m), 2.65 (3H, s), 1.42 (1.5H, d, J=6.8 Hz), 1.28 (1.5H, d,J=6.8 Hz) ppm. ¹⁹F NMR (DMSO-d₆, 376.3 MHz) δ −113.8, −114 ppm.

Example 347-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(2,3-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-6-(2,3-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.12 g, 0.38 mmol) and (2,3-difluorophenyl)boronic acid (0.072 g, 0.46mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodium carbonatein water (0.57 mL, 0.57 mmol) anddichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(0.014 g, 0.019 mmol). The mixture was stirred at 100° C. overnight.After cooling, the mixture was diluted with ethyl acetate, washed withwater, dried over Na₂SO₄, concentrated, and purified on silica gel(0-30% ethyl acetate/hexane) to give the desired product (83 mg). LCMScalculated for C₁₅H₁₂F₂N₅OS (M+H)⁺: m/z=348.1. Found: 348.0.

Step 2.7-(1-aminoethyl)-6-(2,3-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-(1-azidoethyl)-6-(2,3-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.083 g, 0.24 mmol) in tetrahydrofuran (3 mL) was added 1.00 M oftrimethylphosphine in tetrahydrofuran (0.29 mL, 0.29 mmol), and themixture was stirred at room temperature for 1 hour. The mixture wasconcentrated to give the crude product (0.076 g), which was useddirectly in next step. LCMS calculated for C₁₅H₁₄F₂N₃OS (M+H)⁺:m/z=322.1. Found: 322.0.

Step 3.7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(2,3-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of 7-(1-aminoethyl)-6-(2,3-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.038 g, 0.12 mmol), 2-amino-6-bromopurine (0.051 g, 0.24 mmol), andN,N-diisopropylethylamine (0.041 mL, 0.24 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA) to give the desiredproduct as a mixture of two diastereomers (TFA salt). LCMS calculatedfor C₂₀H₁₇F₂N₈OS (M+H)⁺: m/z=455.1. Found: 455.1. ¹H NMR (DMSO-d₆, 400MHz) δ 8.12 (1H, d, J=9.6 Hz), 7.45 (1H, m), 7.30˜7.23 (3H, m),7.18˜7.11 (3H, m), 6.56 (1H, s), 5.16 (1H, m), 2.66 (3H, s), 1.44 (1.5H,d, J=6.8 Hz), 1.30 (1.5H, d, J=6.8 Hz) ppm.

Example 357-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-chloro-5-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-6-(3-chloro-5-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.12 g, 0.38 mmol) and (3-chloro-5-fluorophenyl)boronic acid (0.080 g,0.46 mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodiumcarbonate in water (0.5 mL, 0.5 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol). Themixture was heated at 100° C. overnight. After cooling, the mixture wasdiluted with ethyl acetate, washed with water, dried over Na₂SO₄,concentrated and purified on silica gel (0-25% ethyl acetate/hexanes) togive the desired product (0.077 g, 55%). LCMS calculated forC₁₅H₁₂ClFN₅OS (M+H)⁺: m/z=364.0. Found: 364.0.

Step 2.7-(1-aminoethyl)-6-(3-chloro-5-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-(3-chloro-5-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.077 g, 0.21 mmol) in tetrahydrofuran (3 mL) was added 1.00 M oftrimethylphosphine in tetrahydrofuran (0.25 mL, 0.25 mmol) and themixture was stirred at room temperature for 1 hour. The mixture wasconcentrated to give crude product (0.070 g), which was used directly inthe next step. LCMS calculated for C₁₅H₁₄ClFN₃OS (M+H)⁺: m/z=338.1.Found: 338.0.

Step 3.7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-chloro-5-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of7-(1-aminoethyl)-6-(3-chloro-5-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.035 g, 0.10 mmol), 2-amino-6-bromopurine (0.058 g, 0.27 mmol), andN,N-diisopropylethylamine (0.047 mL, 0.27 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA) to give the desiredproduct as a TFA salt. LCMS calculated for C₂₀H₁₇ClFN₈OS (M+H)⁺:m/z=471.1. Found: 471.0. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.79 (1H, d, J=7.2Hz), 8.16 (1H, s), 7.39 (3H, m), 7.21 (2H, s), 7.18 (1H, m), 7.14 (1H,d, J=1.2 Hz), 5.13 (1H, m), 2.65 (3H, s), 1.37 (3H, d, J=6.8 Hz) ppm.¹⁹F NMR (DMSO-d₆, 376.3 MHz) δ −112 ppm.

Example 366-(3-chlorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of7-(1-aminoethyl)-6-(3-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.045 g, 0.14 mmol), 6-bromo-9H-purine (0.056 g, 0.28 mmol), andN,N-diisopropylethylamine (0.049 mL, 0.28 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA), to give thedesired product as a TFA salt. LCMS calculated for C₂₀H₁₇ClN₇OS (M+H)⁺:m/z=438.1. Found: 438.0. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.29 (1H, s), 7.46(3H, m), 7.37 (1H, m), 7.08 (1H, s), 5.14 (1H, m), 2.64 (3H, s), 1.37(3H, d, J=6.8 Hz) ppm.

Example 376-(3-chloro-5-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of7-(1-aminoethyl)-6-(3-chloro-5-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.035 g, 0.10 mmol), 6-bromo-9H-purine (0.041 g, 0.21 mmol), andN,N-diisopropylethylamine (0.036 mL, 0.21 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA) to give the desiredproduct as a TFA salt. LCMS calculated for C₂₀H₁₆ClFN₇OS (M+H)⁺:m/z=456.1. Found: 456.0. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.52 (1H, br s),8.39 (1H, s), 8.36 (1H, s), 7.43 (1H, d, J=8.0 Hz), 7.33˜7.27 (3H, m),7.10 (1H, s), 5.15 (1H, m), 2.64 (3H, s), 1.41 (3H, d, J=6.8 Hz) ppm.¹⁹F NMR (DMSO-d₆, 376.3 MHz) δ −112 ppm.

Example 387-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(5-fluoropyridin-3-yl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-6-(5-fluoropyridin-3-yl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.12 g, 0.38 mmol) and3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.10g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodiumcarbonate in water (0.57 mL, 0.57 mmol) anddichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(0.014 g, 0.020 mmol). The mixture was heated at 100° C. overnight.After cooling, the mixture was diluted with ethyl acetate, washed withwater, dried over Na₂SO₄, concentrated and purified on silica gel (0-45%ethyl acetate/hexanes) to give the desired product (0.020 g, 16%). LCMScalculated for C₁₄H₁₂FN₆OS (M+H)⁺: m/z=331.1. Found: 331.0.

Step 2.7-(1-aminoethyl)-6-(5-fluoropyridin-3-yl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-(1-azidoethyl)-6-(5-fluoropyridin-3-yl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.020 g, 0.060 mmol) in tetrahydrofuran (3 mL) was added 1.00 M oftrimethylphosphine in tetrahydrofuran (0.079 mL, 0.079 mmol), and themixture was stirred at room temperature for 1 hour. The mixture wasconcentrated to give the crude product (0.018 g), which was useddirectly in next step. LCMS calculated for C₁₄H₁₄FN₄OS (M+H)⁺:m/z=305.1. Found: 305.0.

Step 3.7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(5-fluoropyridin-3-yl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of7-(1-aminoethyl)-6-(5-fluoropyridin-3-yl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(9 mg, 0.03 mmol), 2-amino-6-bromopurine (9.5 mg, 0.044 mmol) andN,N-diisopropylethylamine (0.010 mL, 0.059 mmol) in ethanol (0.3 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on prep-LCMS (XBridge C18 Column, eluting with a gradientof acetonitrile/water containing 0.05% TFA) to give the desired productas a TFA salt. LCMS calculated for C₁₉H₁₇FN₉OS (M+H)⁺: m/z=438.1. Found:438.0. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.82 (1H, br s), 8.59 (1H, d, J=2.8Hz), 8.42 (1H, s), 8.16 (1H, s), 7.77 (1H, dt, J=9.6 and 2.4 Hz),7.22˜7.16 (4H, m), 5.08 (1H, m), 2.66 (3H, s), 1.37 (3H, d, J=6.8 Hz)ppm. ¹⁹F NMR (DMSO-d₆, 376.3 MHz) δ −128 ppm.

Example 397-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(2-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-6-(2-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.12 g, 0.38 mmol) and (2-chlorophenyl)boronic acid (0.072 g, 0.46mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodium carbonatein water (0.57 mL, 0.57 mmol) anddichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(0.014 g, 0.019 mmol). The mixture was stirred at 105° C. overnight.After cooling, the mixture was diluted with ethyl acetate, washed withwater, dried over Na₂SO₄, concentrated, and purified on silica gel(0-30% ethyl acetate/hexanes) to give the desired product (0.062 g).LCMS calculated for C₁₅H₁₃ClN₅OS (M+H)⁺: m/z=346.1. Found: 346.0.

Step 2.7-(1-aminoethyl)-6-(2-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a stirred solution of7-(1-azidoethyl)-6-(2-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.062 g, 0.18 mmol) in tetrahydrofuran (3 mL) was added 1.00 M oftrimethylphosphine in tetrahydrofuran (0.22 mL, 0.22 mmol), and themixture was stirred at room temperature for 1 hour. The mixture wasconcentrated to give the crude product (0.056 g), which was useddirectly in next step. C₁₅H₁₅ClN₃OS (M+H)⁺: m/z=320.1. Found: 320.0.

Step 3.7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(2-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of7-(1-aminoethyl)-6-(2-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.028 g, 0.088 mmol), 2-amino-6-bromopurine (0.037 g, 0.18 mmol), andN,N-diisopropylethylamine (0.030 mL, 0.18 mmol) in ethanol (0.4 mL) washeated at 110° C. overnight. The mixture was filtered and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA) to give twodiastereomers as a TFA salts. On analytic HPLC (Waters SunFire C18,2.1×50 mm, 5 μM; injection volume 24; flow rate 3 mL/min; at gradientfrom 2% to 80% acetonitrile in water containing 0.15% NH₄OH in 3 min):First peak has retention time 1.296 min; LCMS calculated forC₂₀H₁₈ClN₈OS (M+H)⁺: m/z=453.1. Found: 453.0. Second peak has retentiontime 1.431 min; LCMS calculated for C₂₀H₁₈ClN₈OS (M+H)⁺: m/z=453.1.Found: 453.0.

Example 406-(2-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of7-(1-aminoethyl)-6-(2-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.040 g, 0.13 mmol), 6-bromo-9H-purine (0.052 g, 0.26 mmol), andN,N-diisopropylethylamine (0.046 mL, 0.26 mmol) in ethanol (0.5 mL, 8mmol) was heated at 110° C. overnight. The mixture was filtered, and thefiltrate was purified on preparative-LCMS (XBridge C18 Column, elutingwith a gradient of acetonitrile/water containing 0.05% TFA) to give thedesired product as a diasteroisomeric mixture (TFA salt). LCMScalculated for C₂₀H₁₇FN₇OS (M+H)⁺: m/z=422.1. Found: 422.1. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.50 (1H, br s), 8.40 (1H, s), 8.38 (1H, s), 7.50(1H, m), 7.36˜7.25 (3H, m), 7.10 (1H, s), 5.14 (1H, m), 2.64 (3H, s),1.48 (1.5H, d, J=6.8 Hz), 1.34 (1.5H, d, J=6.8 Hz) ppm. ¹⁹F NMR(DMSO-d₆, 376.3 MHz) δ −112, −114 ppm.

Example 416-(2,3-difluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of7-(1-aminoethyl)-6-(2,3-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.038 g, 0.12 mmol), 6-bromo-9H-purine (0.047 g, 0.24 mmol), andN,N-diisopropylethylamine (0.041 mL, 0.24 mmol) in ethanol (0.5 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on prep-LCMS (XBridge C18 Column, eluting with a gradientof acetonitrile/water containing 0.05% TFA), to give the desired productas a mixture of two diastereomers (TFA salt). LCMS calculated forC₂₀H₁₆F₂N₇OS (M+H)⁺: m/z=440.1. Found: 440.0. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.38˜8.34 (3H, m), 7.49˜7.10 (4H, m), 5.12 (1H, m), 2.64 (3H, s), 1.50(1.5H, d, J=6.8 Hz), 1.36 (1.5H, d, J=6.8 Hz) ppm. ¹⁹F NMR (DMSO-d₆,376.3 MHz) δ −137.8, −139.8, −140.0 ppm.

Example 426-(5-fluoropyridin-3-yl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of7-(1-aminoethyl)-6-(5-fluoropyridin-3-yl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(9 mg, 0.03 mmol), 6-bromo-9H-purine (8.8 mg, 0.044 mmol), andN,N-diisopropylethylamine (0.010 mL, 0.059 mmol) in ethanol (0.3 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA), to give thedesired product as a TFA salt. LCMS calculated for C₁₉H₁₆FN₈OS (M+H)⁺:m/z=423.1. Found: 423.1. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.60 (1H, d, J=2.8Hz), 8.47 (1H, s), 8.35 (1H, s), 8.33 (1H, s), 7.82 (1H, d, J=9.6 Hz),7.12 (1H, s), 5.09 (1H, m), 2.64 (3H, s), 1.43 (3H, d, J=6.8 Hz) ppm.¹⁹F NMR (DMSO-d₆, 376.3 MHz) δ −128 ppm.

Example 436-(2-chlorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

A mixture of7-(1-aminoethyl)-6-(2-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.028 g, 0.088 mmol), 6-bromo-9H-purine (0.035 g, 0.18 mmol), andN,N-diisopropylethylamine (0.030 mL, 0.18 mmol) in ethanol (0.4 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA), to give twodiastereomers as a TFA salts. On an analytic HPLC (Waters SunFire C18,2.1×50 mm, 5 μM; injection volume 24; flow rate 3 mL/min; at gradientfrom 2% to 80% acetonitrile in water containing 0.15% NH₄OH in 3 min):First peak has retention time 1.421 min; LCMS calculated forC₂₀H₁₇ClN₇OS (M+H)⁺: m/z=438.1. Found: 438.0. Second peak has retentiontime 1.516 min; LCMS calculated for C₂₀H₁₇ClN₇OS (M+H)⁺: m/z=438.1.Found: 438.0. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.36 (1H, s), 8.32 (1H, s),7.57 (2H, m), 7.44 (2H, m), 7.11 (1H, s), 5.04 (1H, m), 2.64 (1H, s),1.34 (3H, d, J=6.8 Hz) ppm.

Example 446-(3,5-difluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.105 g, 0.327 mmol) (1^(st) peak from Example 23, step 1 chiralseparation), 6-bromo-9H-purine (0.117 g, 0.588 mmol), andN,N-diisopropylethylamine (0.114 mL, 0.654 mmol) in ethanol (1.5 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.15% NH₄OH) to give thedesired product (0.073 g, 51%). LCMS calculated for C₂₀H₁₆F₂N₇OS (M+H)⁺:m/z=440.1. Found: 440.0. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.05 (2H, s), 7.34(1H, br s), 7.18 (1H, m), 7.12 (2H, m), 6.84 (1H, s), 7.01 (1H, s), 5.07(1H, m), 2.43 (3H, s), 1.31 (3H, d, J=7.0 Hz) ppm. ¹⁹F NMR (DMSO-d₆,376.3 MHz) δ −111 ppm.

Example 456-(2,5-difluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

Step 1.7-(1-azidoethyl)-6-(2,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a mixture of7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.080 g, 0.25 mmol) and (2,5-difluorophenyl)boronic acid (0.048 g, 0.30mmol) in 1,4-dioxane (2 mL) was added a 1 N solution of sodium carbonatein water (0.38 mL, 0.38 mmol) anddichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(0.011 g, 0.015 mmol). The mixture was stirred at 100° C. overnight.After cooled to room temperature, the mixture was diluted with ethylacetate, washed with water, dried over MgSO₄, then concentrated andpurified on silica gel (0-25% ethyl acetate/hexane) to give the desiredproduct as a diastereoisomer mixture (54 mg). LCMS calculated forC₁₅H₁₂F₂N₅OS (M+H)⁺: m/z=348.1; Found: 348.0.

Step 2.7-(1-aminoethyl)-6-(2,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

To a solution of7-(1-azidoethyl)-6-(2,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.054 g, 0.16 mmol) in tetrahydrofuran (2 mL) was added 1.00 M oftrimethylphosphine in tetrahydrofuran (0.23 mL, 0.23 mmol), and themixture was stirred at room temperature for 1 hour. The mixture wasconcentrated to give the crude product (45 mg), which was used directlyin the next step. LCMS calculated for C₁₅H₁₄F₂N₃OS (M+H)⁺: m/z=322.1.Found: 322.0.

Step 3.6-(2,5-difluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A mixture of7-(1-aminoethyl)-6-(2,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.045 g, 0.14 mmol), 6-bromo-9H-purine (0.042 g, 0.21 mmol), andN,N-diisopropylethylamine (0.049 mL, 0.28 mmol) in ethanol (0.3 mL) washeated at 110° C. overnight. The mixture was filtered, and the filtratewas purified on preparative-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile/water containing 0.05% TFA), to give thedesired product as a mixture of two diastereomers (TFA salts). LCMScalculated for C₂₀H₁₆F₂N₇OS (M+H)⁺: m/z=440.1. Found: 440.1. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.64 (1H, br s), 8.38 (1H, s), 8.36 (1H, s),7.34˜7.19 (3H, m), 7.08 (1H, m), 5.06 (1H, m), 2.60 (3H, s), 1.46 (1.5H,d, J=6.8 Hz), 1.33 (1.5H, d, J=6.8 Hz) ppm. ¹⁹F NMR (DMSO-d₆, 376.3 MHz)δ −117.8, −119.4, −119.8, −119.9 ppm.

Example 466-(3-Fluorophenyl)-7-[(15)-1-(3H-imidazo[4,5-b]pyridin-7-ylamino)ethyl]3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A solution of7-[(1S)-1-aminoethyl]-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(50 mg, 0.16 mmol), 7-chloro-3H-imidazo[4,5-b]pyridine (51 mg, 0.33mmol), and N,N-diisopropylethylamine (57 μL, 0.33 mmol) in 1-butanol(0.5 mL) in a sealable vial was degassed with nitrogen, sealed, andheated at 140° C. for 48 hours. The reaction mixture was diluted withmethanol and purified by RP-HPLC (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired product (7 mg, 10%) as awhite solid. LCMS for C₂₁H₁₈FN₆OS (M+H)⁺: m/z=420.8. ¹H NMR (400 MHz,CD₃OD): δ 8.04 (s, 1H), 7.83 (d, J=5.9 Hz, 1H), 7.55-7.49 (m, 1H),7.23-7.12 (m, 3H), 6.86 (d, J=1.2 Hz, 1H), 5.96 (d, J=5.9 Hz, 1H),4.69-4.67 (m, 1H), 2.75 (s, 3H), 1.57 (d, J=6.4 Hz, 3H).

Example 476-(3-Fluorophenyl)-7-{(1S)-1-[(2-hydroxy-9H-purin-6-yl)amino]ethyl}-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1.7-{(1S)-1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A solution of7-[(1S)-1-aminoethyl]-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(0.10 g, 0.33 mmol) and 2-amino-6-bromopurine (0.11 g, 0.49 mmol) in1-butanol (0.66 mL) was treated with N,N-diisopropylethylamine (86 μL,0.49 mmol), degassed with nitrogen for 5 min and heated at 100° C. for18 hours. The reaction was not complete and was, therefore, heated at115° C. for an additional 5 hours. The reaction mixture was diluted withmethanol (10 mL), stirred, and filtered. The filtrate was purified byRP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) to give the desired product (27 mg, 19%) as a white solid.LCMS for C₂₀H₁₈FN₈OS (M+H)⁺: m/z=437.0.

Step 2.6-(3-Fluorophenyl)-7-{(1S)-1-[(2-hydroxy-9H-purin-6-yl)amino]ethyl}-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

A solution of7-{(1S)-1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one(27 mg, 62 μmol) in acetic acid (0.41 mL) and water (84 μL) at 0° C. wastreated with a solution of sodium nitrite (13 mg, 0.19 mmol) in water(0.15 mL) dropwise and stirred at 0° C. for 30 minutes and at 20° C. for16 hours. The reaction mixture was concentrated and purified by RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to givethe desired product (7 mg, 20%) as a white solid. LCMS for C₂₀H₁₇FN₇O₂S(M+H)⁺: m/z=437.8. ¹H NMR (300 MHz, DMSO-d₆): δ 7.79 (br s, 1H),7.68-7.61 (m, 1H), 7.50-7.38 (m, 3H), 7.23-7.14 (m, 2H), 7.06 (br s,1H), 5.02-4.92 (m, 1H), 2.64 (s, 3H), 1.26 (d, J=6.7 Hz, 3H).

Example 486-(3-Fluorophenyl)-7-[1-(9H-purin-6-ylamino)ethyl]-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

Step 1.7-(1-Bromoethyl)-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

The desired compound was prepared according to the procedure of Example8, step 2, using 4-(trifluoromethyl)-1,3-thiazol-2-amine as the startingmaterial in 53% yield. LCMS for C₉H₇BrF₃N₂OS (M+H)⁺: m/z=326.8, 328.8.

Step 2.6-Bromo-7-(1-bromoethyl)-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

The desired compound was prepared according to the procedure of Example8, step 3, using7-(1-bromoethyl)-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas the starting material in quantitative yield. LCMS for C₉H₆Br₂F₃N₂OS(M+H)⁺: m/z=404.8, 406.7, 408.7.

Step 3.7-(1-Azidoethyl)-6-bromo-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

The desired compound was prepared according to the procedure of Example8, step 4, using6-bromo-7-(1-bromoethyl)-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas the starting material in 84% yield. LCMS for C₉H₆BrF₃N₅OS (M+H)⁺:m/z=367.7, 369.8.

Step 4.7-(1-Azidoethyl)-6-(3-fluorophenyl)-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

The desired compound was prepared according to the procedure of Example8, step 5, using7-(1-azidoethyl)-6-bromo-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneand (3-fluorophenyl)boronic acid as the starting materials in 29% yield.LCMS for C₁₅H₁₀F₄N₅OS (M+H)⁺: m/z=383.9.

Step 5.7-(1-Aminoethyl)-6-(3-fluorophenyl)-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example8, step 6, using7-(1-azidoethyl)-6-(3-fluorophenyl)-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-oneas the starting material in 79% yield after purification by RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.05% TFA, at flow rate of 30 mL/min). LCMS for C₁₅H₁₂F₄N₃OS(M+H)⁺: m/z=357.9.

Step 6.6-(3-Fluorophenyl)-7-[1-(9H-purin-6-ylamino)ethyl]-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one

The desired compound was prepared according to the procedure of Example8, step 7, using 7-(1-aminoethyl)-6-(3-fluorophenyl)-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-onetrifluoroacetic acid salt as the starting material in 54% yield afterpurification by RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min). LCMS for C₂₀H₁₄F₄N₇OS (M+H)⁺: m/z=475.9. ¹H NMR (300 MHz,DMSO-d₆): δ 8.36 (s, 1H), 8.14-8.08 (m, 2H), 7.55-7.46 (m, 2H),7.32-7.21 (m, 3H), 5.19-5.07 (m, 1H), 1.37 (d, J=7.0 Hz, 3H).

Example 496-Methyl-3-phenyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

Step 1. 2-(1-Bromoethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

The desired compound was prepared according to the procedure of Example8, step 2, using 6-methyl-2-pyridinamine as the starting material in 58%yield. LCMS for C₁₁H₁₂BrN₂O (M+H)⁺: m/z=267.0, 269.0.

Step 2. 2-(1-Bromoethyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

The desired compound was prepared according to the procedure of Example8, step 3, using2-(1-bromoethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one andN-iodosuccinimide as the starting materials in 98% yield. LCMS forC₁₁H₁₁BrIN₂O (M+H)⁺: m/z=392.7, 394.7.

Step 3. 2-(1-Azidoethyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

The desired compound was prepared according to the procedure of Example8, step 4, using2-(1-bromoethyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as thestarting material in 99% yield. LCMS for C₁₁H₁₁IN₅O (M+H)⁺: m/z=356.0.

Step 4.2-(1-Azidoethyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one

A solution of2-(1-azidoethyl)-3-iodo-6-methyl-4H-pyrido[1,2-c]pyrimidin-4-one (100mg, 0.28 mmol) and phenylboronic acid (48 mg, 0.39 mmol) in 1,4-dioxane(2 mL) was treated with sodium carbonate (45 mg, 0.42 mmol), water (0.50mL), anddichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(2.0 mg, 28 μmol), degassed with nitrogen for 5 minutes, and heated at110° C. for 18 hours. The reaction mixture was purified by RP-HPLC(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.05% TFA, at flow rate of 30 mL/min). LCMS for C₁₇H₁₆N₅O(M+H)⁺: m/z=306.1.

Step 5.6-Methyl-3-phenyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

A solution of2-(1-azidoethyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (31mg, 0.10 mmol) in tetrahydrofuran (1 mL) and water (0.2 mL) was treatedwith 1 M of trimethylphosphine in tetrahydrofuran (0.20 mL, 0.20 mmol)and stirred at 20° C. for 1 hour. The reaction mixture was diluted withbrine (2 mL) and extracted with dichloromethane (3×15 mL). The combinedorganic extracts were dried with sodium sulfate, filtered, andconcentrated to a crude residue. This intermediate amine was usedwithout further purification. A solution of the amine in ethanol (1 mL)was treated with 6-bromo-9H-purine (31 mg, 0.16 mmol) andN,N-diisopropylethylamine (24 mL, 0.14 mmol) and then heated at 90° C.for 18 hours. The reaction mixture was purified by RP-HPLC (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.05%TFA, at flow rate of 30 mL/min). LCMS for C₂₂H₂₀N₇O (M+H)⁺: m/z=398.1.

Example 502-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using 2-amino-6-bromopurine (instead of 6-bromo-9H-purine in step 5).LCMS for C₂₂H₂₁H₈O (M+H)⁺: m/z=413.0.

Example 516-Methyl-3-(3-methylphenyl)-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (3-methylphenyl)boronic acid (instead of phenylboronic acid instep 4). LCMS for C₂₃H₂₂N₇O (M+H)⁺: m/z=411.9.

Example 522-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-6-methyl-3-(3-methylphenyl)-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (3-methylphenyl)boronic acid (instead of phenylboronic acid instep 4) and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine in step5). LCMS for C₂₃H₂₃N₈O (M+H)⁺: m/z=427.0.

Example 533-(3-Chlorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (3-chlorophenyl)boronic acid (instead of phenylboronic acid instep 4). LCMS for C₂₂H₁₉ClN₇O (M+H)⁺: m/z=432.1.

Example 542-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(3-chlorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (3-chlorophenyl)boronic acid (instead of phenylboronic acid instep 4) and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine in step5). LCMS for C₂₂H₂₀ClN₈O (M+H)⁺: m/z=447.1.

Example 553-(4-Chlorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (4-chlorophenyl)boronic acid (instead of phenylboronic acid instep 4). LCMS for C₂₂H₁₉ClN₇O (M+H)⁺: m/z=432.1.

Example 562-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(4-chlorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (4-chlorophenyl)boronic acid (instead of phenylboronic acid instep 4) and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine in step5). LCMS for C₂₂H₂₀ClN₈O (M+H)⁺: m/z=447.1.

Example 573-(2-Chlorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (2-chlorophenyl)boronic acid (instead of phenylboronic acid instep 4) as a mixture of atropisomers. LCMS for C₂₂H₁₉ClN₇O (M+H)⁺:m/z=432.1.

Example 582-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(2-chlorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (2-chlorophenyl)boronic acid (instead of phenylboronic acid instep 4) and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine in step5) as a mixture of atropisomers. LCMS for C₂₂H₂₀ClN₈O (M+H)⁺: m/z=447.1.

Example 593-(2-Fluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (2-fluorophenyl)boronic acid (instead of phenylboronic acid instep 4). LCMS for C₂₂H₁₉FN₇O (M+H)⁺: m/z=416.1.

Example 602-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(2-fluorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (2-fluorophenyl)boronic acid (instead of phenylboronic acid instep 4) and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine in step5). LCMS for C₂₂H₂₀FN₈O (M+H)⁺: m/z=431.1.

Example 614-{6-Methyl-4-oxo-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-3-yl}benzonitriletrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (4-cyanophenyl)boronic acid (instead of phenylboronic acid instep 4). LCMS for C₂₃H₁₉N₈O (M+H)⁺: m/z=423.1.

Example 624-(2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)benzonitriletrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (4-cyanophenyl)boronic acid (instead of phenylboronic acid instep 4) and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine in step5). LCMS for C₂₃H₂₀N₉O (M+H)⁺: m/z=438.2.

Example 636-Methyl-3-(2-methylphenyl)-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (2-methylphenyl)boronic acid (instead of phenylboronic acid instep 4), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiumin step 4), and potassium carbonate (instead of sodium carbonate in step4). LCMS for C₂₃H₂₂N₇O (M+H)⁺: m/z=412.1.

Example 646-Methyl-3-(4-methylphenyl)-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (4-methylphenyl)boronic acid (instead of phenylboronic acid instep 4), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiumin step 4), and potassium carbonate (instead of sodium carbonate in step4). LCMS for C₂₃H₂₂N₇O (M+H)⁺: m/z=412.1.

Example 653-(3-Methoxyphenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using 3-methoxyphenylboronic acid (instead of phenylboronic acid instep 4), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiumin step 4), and potassium carbonate (instead of sodium carbonate in step4). LCMS for C₂₃H₂₂N₇O₂ (M+H)⁺: m/z=428.1.

Example 663-(2,3-Difluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (2,3-difluorophenyl)boronic acid (instead of phenylboronic acidin step 4), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiumin step 4), and potassium carbonate (instead of sodium carbonate in step4). LCMS for C₂₂H₁₈F₂N₇O (M+H)⁺: m/z=434.2.

Example 673-(2,5-Difluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (2,5-difluorophenyl)boronic acid (instead of phenylboronic acidin step 4), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiumin step 4), and potassium carbonate (instead of sodium carbonate in step4). LCMS for C₂₂H₁₈F₂N₇O (M+H)⁺: m/z=434.1.

Example 683-(3,4-Difluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (3,4-difluorophenyl)boronic acid (instead of phenylboronic acidin step 4), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiumin step 4), and potassium carbonate (instead of sodium carbonate in step4). LCMS for C₂₂H₁₈F₂N₇O (M+H)⁺: m/z=434.0.

Example 693-(3,5-Difluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (3,5-difluorophenyl)boronic acid (instead of phenylboronic acidin step 4) and tetrakis(triphenylphosphine)palladium(0) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium in step4). LCMS for C₂₂H₁₈F₂N₇O (M+H)⁺: m/z=434.0. ¹H NMR (300 MHz, DMSO-d₆): δ8.80 (br s, 1H), 8.48 (s, 2H), 7.71 (dd, J=7.9, 7.6 Hz, 1H), 7.45 (d,J=8.2 Hz, 1H), 7.24 (d, J=9.7, 9.1 Hz, 1H), 7.18-7.11 (m, 3H), 6.97 (d,J=6.7 Hz, 1H), 5.29-5.20 (m, 1H), 2.89 (s, 3H), 1.46 (d, J=6.7 Hz, 3H).

Example 703-(3-Fluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (3-fluorophenyl)boronic acid (instead of phenylboronic acid instep 4) and tetrakis(triphenylphosphine)palladium(0) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium in step4). LCMS for C₂₂H₁₉FN₇O (M+H)⁺: m/z=416.1. ¹H NMR (300 MHz, DMSO-d₆): δ8.85 (br s, 1H), 8.50 (s, 2H), 7.70 (dd, J=7.9, 7.6 Hz, 1H), 7.51-7.40(m, 2H), 7.27-7.16 (m, 3H), 6.96 (d, J=6.7 Hz, 1H), 5.31-5.20 (m, 1H),2.88 (s, 3H), 1.44 (d, J=6.7 Hz, 3H).

Example 71 and Example 72 Single Enantiomers of3-(3-Fluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

Step 1. Chiral Separation of2-(1-Azidoethyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

The racemic mixture of2-(1-azidoethyl)-3-iodo-6-methyl-4H-pyrido[1,2-c]pyrimidin-4-one wasseparated by HPLC (Chiracel OJ-H, eluting with 30% ethanol/70% hexanes,at flow rate of 20 mL/min) to give the two individual enantiomers(retention times=21.6 min, 27.2 min). Both peaks were advanced to thenext step.

Step 2. Single Enantiomers of2-(1-azidoethyl)-3-(3-fluorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compounds were prepared according to the procedure ofExample 49, step 4, using peak 1 and peak 2 of2-(1-azidoethyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and(3-fluorophenyl)boronic acid as the starting materials afterpurification by RP-HPLC (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min).From peak 1: LCMS for C₁₇H₁₅FN₅O (M+H)⁺: m/z=324.1. From peak 2: LCMSfor C₁₇H₁₅FN₅O (M+H)⁺: m/z=323.9.

Step 3. Single Enantiomers of3-(3-Fluorophenyl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compounds were prepared according to the procedure ofExample 49, step 5, using the single enantiomers of2-(1-azidoethyl)-3-(3-fluorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt and (3-fluorophenyl)boronic acid as thestarting materials. Example 71 (from peak 1): LCMS for C₂₂H₁₉FN₇O(M+H)⁺: m/z=415.9.; ¹H NMR (400 MHz, DMSO-d₆): δ 8.78 (br s, 1H), 8.48(s, 2H), 7.70 (dd, J=7.8, 7.7 Hz, 1H), 7.50-7.41 (m, 2H), 7.28-7.17 (m,3H), 6.96 (d, J=7.0 Hz, 1H), 5.30-5.21 (m, 1H), 2.88 (s, 3H), 1.44 (d,J=6.7 Hz, 3H). Example 72 (from peak 2): LCMS for C₂₂H₁₉FN₇O (M+H)⁺:m/z=416.1.; ¹H NMR (400 MHz, DMSO-d₆): δ 8.78 (br s, 1H), 8.48 (s, 2H),7.70 (dd, J=8.1, 7.5 Hz, 1H), 7.50-7.42 (m, 2H), 7.27-7.18 (m, 3H), 6.96(d, J=6.8 Hz, 1H), 5.30-5.21 (m, 1H), 2.88 (s, 3H), 1.44 (d, J=6.7 Hz,3H).

Example 732-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(3-fluorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using (3-fluorophenyl)boronic acid (instead of phenylboronic acid instep 4), tetrakis(triphenylphosphine)palladium(0) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium in step4), and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine in step 5).LCMS for C₂₂H₂₀FN₈O (M+H)⁺: m/z=431.2. ¹H NMR (300 MHz, DMSO-d₆): δ 8.72(d, J=7.3 Hz, 1H), 8.17 (s, 1H), 7.74-7.68 (m, 1H), 7.50-7.41 (m, 2H),7.29-7.14 (m, 5H), 6.98 (d, J=6.4 Hz, 1H), 5.26-5.17 (m, 1H), 2.89 (s,3H), 1.37 (d, J=6.7 Hz, 3H).

Example 74 and Example 75 Single Enantiomers of2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(3-fluorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compounds were prepared according to the procedure ofExample 71 and 72. 2-amino-6-bromopurine (instead of 6-bromo-9H-purinein step 5). Example 74 (from peak 1): C₂₂H₂₀FN₈O (M+H)⁺: m/z=431.0; ¹HNMR (400 MHz, DMSO-d₆): δ 8.72 (d, J=7.3 Hz, 1H), 8.17 (s, 1H), 7.72(dd, J=8.8, 7.1 Hz, 1H), 7.48-7.40 (m, 2H), 7.27-7.13 (m, 5H), 6.98 (d,J=6.8 Hz, 1H), 5.25-5.18 (m, 1H), 2.89 (s, 3H), 1.37 (d, J=6.7 Hz, 3H).Example 75 (from peak 2): C₂₂H₂₀FN₈O (M+H)⁺: m/z=431.1; ¹H NMR (400 MHz,DMSO-d₆): δ 8.72 (d, J=7.1 Hz, 1H), 8.17 (s, 1H), 7.71 (dd, J=8.9, 7.1Hz, 1H), 7.49-7.42 (m, 2H), 7.28-7.15 (m, 5H), 6.98 (d, J=6.8 Hz, 1H),5.25-5.18 (m, 1H), 2.89 (s, 3H), 1.37 (d, J=6.8 Hz, 3H).

Example 763-(3,5-Difluorophenyl)-6-ethyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using 6-ethylpyridin-2-amine (instead of 6-methyl-2-pyridinamine instep 1), N-bromosuccinimide (instead of N-iodosuccinimide in step 2),(3,5-difluorophenyl)boronic acid (instead of phenylboronic acid in step4), and tetrakis(triphenylphosphine)palladium(0) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiumin step 4). LCMS for C₂₃H₂₀F₂N₇O (M+H)⁺: m/z=448.2. ¹H NMR (300 MHz,DMSO-d₆): δ 8.57-8.44 (m, 1H), 8.40 (s, 2H), 7.75 (dd, J=8.2, 7.9 Hz,1H), 7.48 (d, J=8.8 Hz, 1H), 7.29-7.12 (m, 3H), 7.04 (d, J=6.7 Hz, 1H),5.30-5.17 (m, 1H), 3.33 (q, J=7.0 Hz, 2H), 1.45 (d, J=6.7 Hz, 3H), 1.14(t, J=7.0 Hz, 3H).

Example 772-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(3,5-difluorophenyl)-6-ethyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using 6-ethylpyridin-2-amine (instead of 6-methyl-2-pyridinamine instep 1), N-bromosuccinimide (instead of N-iodosuccinimide in step 2),(3,5-difluorophenyl)boronic acid (instead of phenylboronic acid in step4), tetrakis(triphenylphosphine)palladium(0) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiumin step 4) and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine instep 5). LCMS for C₂₃H₂₁F₂N₈O (M+H)⁺: m/z=463.2. ¹H NMR (300 MHz,DMSO-d₆): δ 8.74-8.69 (m, 1H), 8.17 (s, 1H), 7.78 (dd, J=8.8, 7.0 Hz,1H), 7.50 (d, J=8.5 Hz, 1H), 7.32-7.16 (m, 3H), 7.14-7.04 (m, 2H),5.26-5.16 (m, 1H), 3.35 (q, J=7.3 Hz, 2H), 1.41 (d, J=6.7 Hz, 3H), 1.15(t, J=7.3 Hz, 3H).

Example 786-Ethyl-3-(4-fluorophenyl)-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using 6-ethylpyridin-2-amine (instead of 6-methyl-2-pyridinamine instep 1), N-bromosuccinimide (instead of N-iodosuccinimide in step 2),(4-fluorophenyl)boronic acid (instead of phenylboronic acid in step 4),and tetrakis(triphenylphosphine)palladium(0) (instead of dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium in step4). LCMS for C₂₃H₂₁FN₇O (M+H)⁺: m/z=430.2.

Example 793-(3,5-Difluorophenyl)-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using 2-pyridinamine (instead of 6-methyl-2-pyridinamine in step 1),N-bromosuccinimide (instead of N-iodosuccinimide in step 2),(3,5-difluorophenyl)boronic acid (instead of phenylboronic acid in step4), and tetrakis(triphenylphosphine)palladium(0) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium in step4). LCMS for C₂₁H₁₆F₂N₇O (M+H)⁺: m/z=420.0. ¹H NMR (300 MHz, DMSO-d₆): δ8.96 (d, J=7.3 Hz, 1H), 8.36 (s, 2H), 8.01 (dd, J=8.2, 7.3 Hz, 1H), 7.74(d, J=8.8 Hz, 1H), 7.40 (dd, J=6.7, 6.4 Hz, 1H), 7.32-7.16 (m, 3H),5.37-5.26 (m, 1H), 1.46 (d, J=6.7 Hz, 3H).

Example 802-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(3,5-difluorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using 2-pyridinamine (instead of 6-methyl-2-pyridinamine in step 1),N-bromosuccinimide (instead of N-iodosuccinimide in step 2),(3,5-difluorophenyl)boronic acid (instead of phenylboronic acid in step4), tetrakis(triphenylphosphine)palladium(0) (instead of dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium in step4) and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine in step 5).LCMS for C₂₁H₁₇F₂N₈O (M+H)⁺: m/z=435.0. ¹H NMR (300 MHz, DMSO-d₆): δ8.98 (d, J=7.0 Hz, 1H), 8.82-8.72 (br s, 1H), 8.17 (s, 1H), 8.06-8.00(m, 1H), 7.76 (d, J=9.1 Hz, 1H), 7.43 (dd, J=7.0, 5.6 Hz, 1H), 7.30-7.07(m, 5H), 5.32-5.22 (m, 1H), 1.42 (d, J=6.7 Hz, 3H).

Example 813-(6-Chloro-5-methylpyridin-3-yl)-6-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using N-bromosuccinimide (instead of N-iodosuccinimide in step 2),(6-chloro-5-methylpyridin-3-yl)boronic acid (instead of phenylboronicacid in step 4), and tetrakis(triphenylphosphine)palladium(0) (insteadof dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium in step4). LCMS for C₂₂H₂₀ClN₈O (M+H)⁺: m/z=446.9. ¹H NMR (300 MHz, DMSO-d₆): δ8.37 (br s, 2H), 8.26 (s, 1H), 7.82 (s, 1H), 7.71 (dd, J=9.1, 7.0 Hz,1H), 7.45 (d, J=8.8 Hz, 1H), 6.97 (d, J=6.2 Hz, 1H), 5.21-5.10 (m, 1H),2.88 (s, 3H), 2.33 (s, 3H), 1.45 (d, J=6.7 Hz, 3H).

Example 822-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-3-(6-chloro-5-methylpyridin-3-yl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-onetrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using N-bromosuccinimide (instead of N-iodosuccinimide in step 2),(6-chloro-5-methylpyridin-3-yl)boronic acid (instead of phenylboronicacid in step 4), tetrakis(triphenylphosphine)palladium(0) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium in step4), and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine in step 5).LCMS for C₂₂H₂₁ClN₉O (M+H)⁺: m/z=462.0. ¹H NMR (500 MHz, DMSO-d₆): δ8.74 (br s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.79-7.71 (m, 2H), 7.50 (d,J=8.8 Hz, 1H), 7.29-7.14 (m, 2H), 7.03 (d, J=6.9 Hz, 1H), 5.23-5.16 (m,1H), 2.92 (s, 3H), 2.31 (s, 3H), 1.43 (d, J=6.7 Hz, 3H).

Example 833-{6-Methyl-4-oxo-2-[1-(9H-purin-6-ylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-3-yl}benzonitriletrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using N-bromosuccinimide (instead of N-iodosuccinimide in step 2),(3-cyanophenyl)boronic acid (instead of phenylboronic acid in step 4),and tetrakis(triphenylphosphine)palladium(0) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiumin step 4). LCMS for C₂₃H₁₉N₈O (M+H)⁺: m/z=422.9. ¹H NMR (500 MHz,DMSO-d₆): δ 8.46 (br s, 1H), 8.40 (s, 2H), 7.91-7.83 (m, 2H), 7.81-7.76(m, 1H), 7.75-7.69 (m, 1H), 7.69-7.63 (m, 1H), 7.48 (d, J=8.7 Hz, 1H),6.98 (d, J=6.7 Hz, 1H), 5.24-5.15 (br s, 1H), 2.91 (s, 3H), 1.46 (d,J=6.6 Hz, 3H).

Example 843-(2-{1-[(2-Amino-9H-purin-6-yl)amino]ethyl}-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)benzonitriletrifluoroacetic acid salt

The desired compound was prepared according to the procedure of Example49 using N-bromosuccinimide (instead of N-iodosuccinimide in step 2),(3-cyanophenyl)boronic acid (instead of phenylboronic acid in step 4),tetrakis(triphenylphosphine)palladium(0) (instead ofdichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladiumin step 4), and 2-amino-6-bromopurine (instead of 6-bromo-9H-purine instep 5). LCMS for C₂₃H₂₀N₉O (M+H)⁺: m/z=438.0. ¹H NMR (500 MHz,DMSO-d₆): δ 8.73 (br s, 1H), 8.18 (s, 1H), 7.84-7.80 (m, 2H), 7.78-7.71(m, 2H), 7.64 (dd, J=8.2, 8.0 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.24 (brs, 2H), 7.01 (d, J=6.9 Hz, 1H), 5.21-5.15 (m, 1H), 2.92 (s, 3H), 1.40(d, J=6.7 Hz, 3H).

Example A1 PI3K Enzyme Assay

PI3-Kinase luminescent assay kit including lipid kinase substrate,D-myo-phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D(+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked (PIP2),biotinylated I(1,3,4,5)P4, PI(3,4,5)P3 Detector Protein, was purchasedfrom Echelon Biosciences (Salt Lake City, Utah). AlphaScreen™ GSTDetection Kit including donor and acceptor beads was purchased fromPerkinElmer Life Sciences (Waltham, Mass.). PI3Kδ (p110δ/p85α) waspurchased from Millipore (Bedford, Mass.). ATP, MgCl₂, DTT, EDTA, HEPESand CHAPS were purchased from Sigma-Aldrich (St. Louis, Mo.).

AlphaScreen™ Assay for PI3Kδ

The kinase reaction was conducted in 384-well REMP plate from ThermoFisher Scientific in a final volume of 40 μL. Inhibitors were firstdiluted serially in DMSO and added to the plate wells before theaddition of other reaction components. The final concentration of DMSOin the assay was 2%. The PI3K assays were carried out at roomtemperature in 50 mM HEPES, pH 7.4, 5 mM MgCl₂, 50 mM NaCl, 5 mM DTT andCHAPS 0.04%. Reactions were initiated by the addition of ATP, the finalreaction mixture consisted of 20 μM PIP2, 20 μM ATP, 1.2 nM PI3Kδ wereincubated for 20 min. 10 μL of reaction mixture was then transferred to5 μL 50 nM biotinylated I(1,3,4,5)P4 in quench buffer: 50 mM HEPES pH7.4, 150 mM NaCl, 10 mM EDTA, 5 mM DTT, 0.1% Tween-20, followed with theaddition of 10 μL AlphaScreen™ donor and acceptor beads suspended inquench buffer containing 25 nM PI(3,4,5)P3 detector protein. The finalconcentration of both donor and acceptor beads is 20 mg/ml. After platesealing, the plate was incubated in a dark location at room temperaturefor 2 hours. The activity of the product was determined on Fusion-alphamicroplate reader (Perkin-Elmer). IC₅₀ determination was performed byfitting the curve of percent control activity versus the log of theinhibitor concentration using the GraphPad Prism 3.0 software.

Example A2 PI3K Enzyme Assay

Materials:

Lipid kinase substrate, phosphoinositol-4,5-bisphosphate (PIP2), waspurchased from Echelon Biosciences (Salt Lake City, Utah). PI3K isoformsα, β, δ and γ were purchased from Millipore (Bedford, Mass.). ATP,MgCl₂, DTT, EDTA, MOPS and CHAPS were purchased from Sigma-Aldrich (St.Louis, Mo.).

The kinase reaction was conducted in clear-bottom 96-well plate fromThermo Fisher Scientific in a final volume of 24 μL Inhibitors werefirst diluted serially in DMSO and added to the plate wells before theaddition of other reaction components. The final concentration of DMSOin the assay was 0.5%. The PI3K assays were carried out at roomtemperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mM DTT and CHAPS0.03%. The reaction mixture was prepared containing 50 μM PIP2, kinaseand varying concentration of inhibitors. Reactions were initiated by theaddition of ATP containing 2.2 μCi [γ-³³P]ATP to a final concentrationof 1000 μM. The final concentration of PI3K isoforms α, β, δ and γ inthe assay were 1.3, 9.4, 2.9 and 10.8 nM respectively. Reactions wereincubated for 180 min and terminated by the addition of 100 μL of 1 Mpotassium phosphate pH 8.0, 30 mM EDTA quench buffer. A 100 μL aliquotof the reaction solution was then transferred to 96-well MilliporeMultiScreen IP 0.45 μm PVDF filter plate (The filter plate was prewettedwith 200 μL 100% ethanol, distilled water, and 1 M potassium phosphatepH 8.0, respectively). The filter plate was aspirated on a MilliporeManifold under vacuum and washed with 18×200 μL wash buffer containing 1M potassium phosphate pH 8.0 and 1 mM ATP. After drying by aspirationand blotting, the plate was air dried in an incubator at 37° C.overnight. Packard TopCount adapter (Millipore) was then attached to theplate followed with addition of 120 μL Microscint 20 scintillationcocktail (Perkin Elmer) in each well. After the plate sealing, theradioactivity of the product was determined by scintillation counting onTopcount (Perkin-Elmer). IC₅₀ determination was performed by fitting thecurve of percent control activity versus the log of the inhibitorconcentration using the GraphPad Prism 3.0 software. Compounds havingand IC₅₀ value of 10 μM or less are considered active. See Table 1 fordata related to compounds of the invention.

Example A3 P131δ Scintillation Proximity Assay Materials

[γ-³³P]ATP (10 mCi/mL) was purchased from Perkin-Elmer (Waltham, Mass.).Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate(PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked(PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (SaltLake City, Utah). PI3Kδ (p110δ/p85α) was purchased from Millipore(Bedford, Mass.). ATP, MgCl₂, DTT, EDTA, MOPS and CHAPS were purchasedfrom Sigma Aldrich (St. Louis, Mo.). Wheat Germ Agglutinin (WGA) YSi SPAScintillation Beads was purchased from GE healthcare life sciences(Piscataway, N.J.).

The kinase reaction was conducted in polystyrene 384-well matrix whiteplate from Thermo Fisher Scientific in a final volume of 25 μL.Inhibitors were first diluted serially in DMSO and added to the platewells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 0.5%. The PI3K assays werecarried out at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mMDTT and CHAPS 0.03%. Reactions were initiated by the addition of ATP,the final reaction mixture consisted of 20 μM PIP2, 20 μM ATP, 0.2 μCi[γ-³³P] ATP, 4 nM PI3Kδ. Reactions were incubated for 210 min andterminated by the addition of 40 μL, SPA beads suspended in quenchbuffer: 150 mM potassium phosphate pH 8.0, 20% glycerol. 25 mM EDTA, 400μM ATP. The final concentration of SPA beads was 1.0 mg/mL. After theplate sealing, plates were shaken overnight at room temperature andcentrifuged at 1800 rpm for 10 minutes, the radioactivity of the productwas determined by scintillation counting on Topcount (Perkin-Elmer).IC₅₀ determination was performed by fitting the curve of percent controlactivity versus the log of the inhibitor concentration using theGraphPad Prism 3.0 software.

TABLE 1 IC₅₀ data for PI3Kδ enzyme assays A1, A2, or A3* PI3Kδ^(a)PI3Kδ^(b) PI3Kα^(c) PI3Kβ^(c) PI3Kγ^(c) Example IC₅₀ (nM) IC₅₀ (nM) IC₅₀(nM) IC₅₀ (nM) IC₅₀ (nM) 1 +++ +++ 2 ++ + 3 +++ +++ 4 +++ ++ 5 +++ ++ 6+++ +++ 7 +++ ++ 8 ++ + 9 + + ++++ ++++ ++ 10 + + ++++ ++++ ++++ 11 + +++++ ++++ +++ 12 + + 13 + + ++++ ++++ +++ 14 ++ ++ 15 + + ++++ ++++ ++++17 +++ 18 +++ 19 +++ 20 + 21 + 22 ++ 23 + ++++ 24 ++++ 25 ++++ 26 +++ 27+++ 28 ++++ 29 ++++ 30 + + ++++ ++++ ++++ 31 +++ 32 ++ 33 + 34 + 35 ++36 +++ 37 +++ 38 ++ 39 1^(st) peak: +++ 2^(nd) peak: + 40 + 41 ++ 42 +++43 1^(st) peak: +++ 2^(nd) peak: + 44 + + ++++ ++++ ++++ 45 + 46 + 47+++ 48 ++ 49 + 50 + 51 +++ 52 + 53 +++ 54 + 55 ++++ 56 ++++ 57 + 58 +59 + 60 + 61 ++++ 62 +++ 63 +++ 64 + 65 + 66 + 67 + 68 +++ 69 +++ 70 ++71 + ++++ 72 ++++ 73 + 74 + 75 ++++ 76 +++ 77 ++ 78 + 79 ++++ 80 +++ 81++++ 82 ++++ 83 +++ 84 ++ *“+” = <50 nM; “++” = 50-100 nM; “+++” =100-500 nM; “++++” = >500 nM. ^(a)Results in this column were obtainedby Assay A1, except for Examples 15, 30 and 44 which used Assay A2.^(b)Results in this column were obtained by Assay A3. ^(c)Results inthis column were obtained by Assay A2.

Example B1 B Cell Proliferation Assay

To acquire B cells, human PBMC were isolated from the peripheral bloodof normal, drug free donors by standard density gradient centrifugationon Ficoll-Hypague (GE Healthcare, Piscataway, N.J.) and incubated withanti-CD19 microbeads (Miltenyi Biotech, Auburn, Calif.). The B cellswere then purified by positive immunosorting using an autoMacs (MiltenyiBiotech) according to the manufacturer's instruction.

The purified B cells (2×10⁵/well/200 μL) were cultured in 96-wellultra-low binding plates (Corning, Corning, N.Y.) in RPMI1640, 10% FBSand goat F(ab′)2 anti-human IgM (10 μg/m1) (Invitrogen, Carlsbad,Calif.), in the presence of different amount of test compounds, forthree days. [³H]-thymidine (1 μCi/well) (PerkinElmer, Boston, Mass.) inPBS was then added to the B cell cultures for an additional 12 hrsbefore the incorporated radioactivity was separated by filtration withwater through GF/B filters (Packard Bioscience, Meriden, Conn.) andmeasured by liquid scintillation counting with a TopCount (PackardBioscience). Compounds having and IC₅₀ value of 10 μM or less areconsidered active. See Table 2 for data related to compounds of theinvention.

TABLE 2 IC₅₀ data for B cell proliferation assay* B cell Example IC₅₀(nM) 1 + 2 +++ 3 + 4 + 5 + 6 ++ 7 ++++ 8 + 9 + 10 + 11 + 12 + 13 + 15 +30 + 44 + 71 + *“+” = <50 nM; “++” = 50-100 nM; “+++” = 100-500 nM;“++++” = >500 nM.

Example B2 Pfeiffer Cell Proliferation Assay

Pfeiffer cell line (diffuse large B cell lymphoma) was purchased fromATCC (Manassas, Va.) and maintained in the culture medium recommended(RPMI and 10% FBS). To measure the anti-proliferation activity of thePI3Kδ submittals, the Pfeiffer cells were plated with the culture medium(2×10³ cells/well/per 200 μl) into 96-well ultra-low binding plates(Corning, Corning, N.Y.), in the presence or absence of a concentrationrange of test compounds. After 3-4 days, [³H]-thymidine (1 μCi/well)(PerkinElmer, Boston, Mass.) in PBS was then added to the cell culturefor an additional 12 hrs before the incorporated radioactivity wasseparated by filtration with water through GF/B filters (PackardBioscience, Meridenj, Conn.) and measured by liquid scintillationcounting with a TopCount (Packard Bioscience). See Table 3 for datarelated to compounds of the invention.

TABLE 3 IC₅₀ data for Pfeiffer cell proliferation assay* Example IC₅₀(nM) 1 +++ 2 + 3 +++ 4 +++ 5 ++ 6 +++ 7 ++++ 8 + 9 + 10 + 11 + 12 +++13 + 14 +++++ 15 + 17 +++ 18 ++ 19 +++++ 20 ++ 21 ++ 22 +++ 23 + 24 +++25 ++++ 27 +++ 30 + 31 +++ 32 + 33 + 34 + 35 + 36 ++ 37 ++ 38 ++ 39First peak: +++ Second peak: + 40 ++ 41 ++ 42 +++ 43 First peak: +++Second peak: + 44 + 45 ++ 46 + 48 ++ 49 ++ 50 + 51 +++ 52 ++ 53 ++ 54 ++57 ++ 58 + 59 +++ 60 ++ 62 ++++ 63 +++ 64 ++ 65 ++ 66 +++ 67 ++ 68 ++++69 ++ 70 + 71 + 72 ++++ 73 + 74 + 75 ++++ 76 +++ 77 + 78 +++ 80 +++ 83+++ 84 +++ *“+” = <50 nM; “++” = 50-100 nM; “+++” = 100-500 nM; “++++” =500-1000 nM; “+++++” = >1000 nM.

Example C Akt Phosphorylation Assay

Ramos cells (B lymphocyte from Burkitts lymphoma) were obtained fromATCC (Manassas, Va.) and maintained in RPMI1640 and 10% FBS. The cells(3×10⁷ cells/tube/3 mL in RPMI) were incubated with different amounts oftest compounds for 2 hrs at 37° C. and then stimulated with goat F(ab′)2anti-human IgM (5 μg/mL) (Invitrogen) for 17 min. in a 37° C. waterbath. The stimulated cells were spun down at 4° C. with centrifugationand whole cell extracts prepared using 300 μL lysis buffer (CellSignaling Technology, Danvers, Mass.). The resulting lysates weresonicated and supernatants were collected. The phosphorylation level ofAkt in the supernatants were analyzed by using PathScan phospho-Aktl(Ser473) sandwich ELISA kits (Cell Signaling Technology) according tothe manufacturer's instruction.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1-32. (canceled)
 33. A compound of Formula IId:

or pharmaceutically acceptable salt thereof, wherein: A is aryl,heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); R¹ is NR^(A)R^(B);R^(2a) is H, halo, OH, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein saidC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); R³ and R⁴ areindependently selected from H, halo, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)₂NR^(c3)R^(d3), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(e))NR^(c3)R^(d3),NR^(c3)C(═NR^(e))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3); R^(A) is heteroaryl, heterocycloalkyl,heteroarylalkyl, or heterocycloalkylalkyl, each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from —(C₁₋₄alkyl)_(r)-Cy¹, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);R^(B) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, 3, 4, or 5 substituents independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR)NR^(c5)R^(d5), NR^(c5)C(═NR)NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5); Cy¹ is aryl,heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substitutedby 1, 2, 3, 4, or 5 substituents independently selected from halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1)OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); R^(a), R^(b),R^(c), and R^(d) are independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, 3, 4, or 5 substituents independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR)NR^(c5)R^(d5), NR^(c5)C(═NR^(f))NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5); or R^(c) and R^(d)together with the N atom to which they are attached form a 3-, 4-, 5-,6-, or 7-membered heterocycloalkyl group or a heteroaryl group, eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR)NR^(c5)R^(d5),NR^(c5)C(═NR)NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);R^(a1), R^(b1), R^(c1), and R^(d1) are independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR)NR^(c5)R^(d5), NR^(c5)C(═NR)NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5); or R^(c1) and R^(d1)together with the N atom to which they are attached form a 3-, 4-, 5-,6-, or 7-membered heterocycloalkyl group or a heteroaryl group, eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR^(f))NR^(c5)R^(d5),NR^(c5)C(═NR)NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);R^(a2), R^(b2), R^(c2), and R^(d2) are independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), C(═NR)NR^(c5)R^(d5), NR^(c5)C(═NR^(f))NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5); or R^(c2) and R^(d2)together with the N atom to which they are attached form a 3-, 4-, 5-,6-, or 7-membered heterocycloalkyl group or a heteroaryl group, eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NRf)NR^(c5)R^(d5),NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), andS(O)₂NR^(c5)R^(d5); R^(a3), R^(b3), R^(a3), and R^(d3) are independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), C(═NR)NR^(c5)R^(d5),NR^(c5)C(═NR)NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5);or R^(c3) and R^(d3) together with the N atom to which they are attachedform a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or aheteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, halo, C₁₋₆haloalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR)NR^(c5)R^(d5), NR^(c5)C(═NR)NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5); R^(e) and R^(f) areindependently selected from H, CN, NO₂, OR^(a5), SR^(b5), S(O)₂R^(b5),C(O)R^(b5), S(O)₂NR^(c5)R^(d5), and C(O)NR^(c5)R^(d5); R^(a5), R^(b5),R^(c5), and R^(d5) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, C₁₋₆ haloalkyl, andC₁₋₆ haloalkoxy; or R^(c5) and R^(d5) together with the N atom to whichthey are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkylgroup or heteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy; and r is 0 or 1.34-37. (canceled)
 38. The compound of claim 33, or a pharmaceuticallyacceptable salt thereof, wherein A is aryl optionally substituted with1, 2, 3, 4, or 5 substituents independently selected from halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).
 39. The compound ofclaim 33, or a pharmaceutically acceptable salt thereof, wherein A isphenyl optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).
 40. The compound ofclaim 33, or a pharmaceutically acceptable salt thereof, wherein A isphenyl optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.
 41. Thecompound of claim 33, or a pharmaceutically acceptable salt thereof,wherein A is phenyl.
 42. The compound of claim 33, or a pharmaceuticallyacceptable salt thereof, wherein A is heteroaryl optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).
 43. The compound ofclaim 33, or a pharmaceutically acceptable salt thereof, wherein A is6-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).
 44. The compound ofclaim 33, or a pharmaceutically acceptable salt thereof, wherein A ispyridyl optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, C₁₋₆ alkyl, or C₁₋₆ haloalkyl. 45-54.(canceled)
 55. The compound of claim 33, or a pharmaceuticallyacceptable salt thereof, wherein R^(A) is purinyl optionally substitutedwith 1 or 2 substituents independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5),NR^(c5)C(O)OR^(a5), NR^(c5)C(═NR^(f))NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5).
 56. The compound ofclaim 33, or a pharmaceutically acceptable salt thereof, wherein R^(A)is:

57-58. (canceled)
 59. The compound of claim 33, or a pharmaceuticallyacceptable salt thereof, wherein R^(B) is H. 60-62. (canceled)
 63. Thecompound of claim 33, or a pharmaceutically acceptable salt thereof,wherein R^(2a) is methyl or ethyl. 64-67. (canceled)
 68. The compound ofclaim 33, or a pharmaceutically acceptable salt thereof, wherein R³ ismethyl. 69-70. (canceled)
 71. The compound of claim 33, or apharmaceutically acceptable salt thereof, wherein R⁴ is H. 72-75.(canceled)
 76. The compound of claim 33, or a pharmaceuticallyacceptable salt thereof, having Formula IIg:

wherein R⁸ and R⁹ are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5),C(═NR^(f))NR^(c5)R^(d5), NR^(c5)C(═NR^(f))NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5).
 77. The compound ofclaim 33, or a pharmaceutically acceptable salt thereof; wherein: A isaryl or heteroaryl, each optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, and OR^(a); R¹ is NR^(A)R^(B); R^(2a) is C₁₋₆ alkyl; R³and R⁴ are independently selected from H, halo, CN, NO₂, OR^(a3), andC₁₋₆ alkyl; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from halo; R^(A) isheteroaryl, which is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, CN, OR^(a1),and NR^(c1)R^(d1); R^(B) is H; each R^(a) is independently selected fromH and C₁₋₆ alkyl; each R^(a1), R^(c1), and R^(d1) is independentlyselected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo; and each R^(a3) is independently selected from H and C₁₋₆alkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, 3,4, or 5 substituents independently selected from halo.
 78. The compoundof claim 77, or a pharmaceutically acceptable salt thereof, wherein: Ais phenyl, 5-membered heteroaryl or 6-membered heteroaryl, eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, and OR^(a); R¹ isNR^(A)R^(B); R^(2a) is C₁₋₆ alkyl; R³ and R⁴ are independently selectedfrom H, halo, CN, NO₂, OR^(a3), and C₁₋₆ alkyl; wherein said C₁₋₆ alkylis optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halo; R^(A) is selected from:

R^(B) is H; each R^(a) is independently selected from H and C₁₋₆ alkyl;and each R^(a3) is independently selected from H and C₁₋₆ alkyl, whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo.
 79. The compound of claim33, selected from:3-methyl-6-phenyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-3-methyl-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(3-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(3,5-difluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;and3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one,or a pharmaceutically acceptable salt of any of the aforementioned. 80.The compound of claim 33, selected from:6-(3,5-difluorophenyl)-3-methyl-7-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(3,5-difluorophenyl)-7-{1-[(2-fluoro-9H-purin-6-yl)amino]ethyl}-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-pyridin-4-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-[1,3]-thiazol-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-6-[1,3]-thiazol-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(4-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(3,5-difluorophenyl)-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(3-fluorophenyl)-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-phenyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;3-methyl-6-(4-methylphenyl)-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(2-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(2,3-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(3-chloro-5-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(3-chlorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(3-chloro-5-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(5-fluoropyridin-3-yl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;7-{1-[(2-amino-9H-purin-6-yl)amino]ethyl}-6-(2-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(2-fluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(2,3-difluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(5-fluoropyridin-3-yl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(2-chlorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(2,5-difluorophenyl)-3-methyl-7-[1-(9H-purin-6-ylamino)ethyl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(3-Fluorophenyl)-7-[(1S)-1-(3H-imidazo[4,5-b]pyridin-7-ylamino)ethyl]-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;6-(3-Fluorophenyl)-7-{(1S)-1-[(2-hydroxy-9H-purin-6-yl)amino]ethyl}-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;and6-(3-Fluorophenyl)-7-[1-(9H-purin-6-ylamino)ethyl]-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one;or a pharmaceutically acceptable salt of any of the aforementioned. 81.The compound of claim 33, wherein the compound is(S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;or a pharmaceutically acceptable salt thereof.
 82. A compositioncomprising a compound according to claim 33, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.
 83. A method of inhibiting an activity of PI3Kδ comprisingcontacting said PI3Kδ with a compound of claim 33, or a pharmaceuticallyacceptable salt thereof. 84-86. (canceled)
 87. The method of claim 83,wherein said compound is a selective inhibitor for PI3Kδ over one ormore of PI3Kα, PI3Kβ, and PI3Kγ.
 88. A method of treating a disease in apatient, wherein said disease is associated with abnormal expression oractivity of a PI3K kinase, comprising administering to said patient atherapeutically effective amount of a compound of claim 33, or apharmaceutically acceptable salt thereof.
 89. The method of claim 88,wherein said disease is osteoarthritis, restenosis, atherosclerosis,bone disorders, arthritis, diabetic retinopathy, psoriasis, benignprostatic hypertrophy, inflammation, angiogenesis, pancreatitis, kidneydisease, inflammatory bowel disease, myasthenia gravis, multiplesclerosis, or Sjoegren's syndrome. 90-93. (canceled)
 94. A method oftreating an immune-based disease, cancer, or lung disease in a patient,comprising administering to said patient a therapeutically effectiveamount of a compound of claim 33, or a pharmaceutically acceptable saltthereof.
 95. The method of claim 94 wherein said immune-based disease isrheumatoid arthritis, allergy, asthma, glomerulonephritis, lupus, orinflammation related to any of the aforementioned.
 96. A method oftreating a cancer in a patient, comprising administering to said patienta therapeutically effective amount of a compound of claim 33, or apharmaceutically acceptable salt thereof.
 97. The method of claim 96,wherein said cancer is breast, prostate, colon, endometrial, brain,bladder, skin, uterus, ovary, lung, pancreatic, renal, gastric, or ahematological cancer.
 98. The method of claim 97, wherein saidhematological cancer is acute myeloblastic leukemia, chronic myeloidleukemia, or B cell lymphoma.
 99. A method of treating a lung disease ina patient, comprising administering to said patient a therapeuticallyeffective amount of a compound of claim 33, or a pharmaceuticallyacceptable salt thereof.
 100. The method of claim 99 wherein said lungdisease is acute lung injury (ALI) or adult respiratory distresssyndrome (ARDS).